Conditions: Prostate Cancer Bladder Cancer Kidney Cancer
Keywords: Lymph Node Biopsy Metastatic Nodes Imaging Agent
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 43
Healthy volunteers: no

Brief summary:
Background:

People with prostate, bladder, or kidney cancer often have their cancer spread (metastasize) to lymph nodes. It is important for your doctor to know if this has occurred but currently it can be hard to determine if this has occurred on standard imaging studies like computed tomography (CT) or magnetic resonance imaging (MRI). This study uses an agent called Ferumoxytol to identify lymph nodes that might be involved by cancer.

Objective:

\- To see how well Ferumoxytol can detect lymph node metastases in patients with prostate, bladder, or kidney cancer.

Eligibility:

-Adults over age 18 with prostate, bladder, or kidney cancer with lymph node involvement.

Design:

* Participants will be screened with a medical history.
* Participants will have blood drawn and a physical exam. Their vital signs will be measured. They will answer questions about their health and current medications.
* Participants should not have a history of iron overload or have an allergy to Ferumoxytol.
* Participants will have a magnetic resonance imaging (MRI) scan. The scanner is a metal cylinder with a strong magnetic field. Participants will lie on a table that slides in and out of the scanner. They will have a standard sensor, known as a coil, wrapped around their abdomen to improve the scan. This is like a small blanket with wiring inside. Participants will need to lie still on the scanning table for about 1 hour.
* Participants will have an ultrasound. This uses harmless sound waves to provide pictures of organs or tissues inside the body.
* Participants will receive an injection of Ferumoxytol through an intravenous line. A very thin plastic tube will be inserted into a vein in order to inject the agent.
* Participants will have another MRI and ultrasound 24 and 48 hours after injection.
* The study will follow participants medical course for at least 1 year.

Detailed description:
Background:

* Conventional imaging modalities (e.g. computed tomography \[CT\] and magnetic resonance imaging \[MRI\]) are currently used for the detection of lymph node metastases in many cancer types, including prostate, bladder and kidney cancers, however diagnosis is based on node enlargement which is neither sensitive nor specific (i.e. small nodes harbor metastases, large nodes can be hyperplastic).
* As a consequence, the standard of care is to remove numerous lymph nodes during surgery or to biopsy enlarged nodes to ascertain lymph node status.
* In 2003 Dextran coated ultra small superparamagnetic iron oxide particles (USPIO), also known as Ferumoxtran-10 (Combidex, AMAG Pharmaceuticals, Inc. Lexington, Massachusetts (MA), United States (US)) was shown to localize lymph node metastases with much greater accuracy than unenhanced MRI. Although a large study in prostate cancer was successful, and Food and Drug Administration (FDA) Advisory Panel did not recommend approval and the company abandoned the agent.
* In 2009 Ferumoxytol (Feraheme AMAG Pharmaceuticals, Inc. Lexington, MA, United States (US)) a semi-synthetic carbohydrate coated, magnetic iron oxide preparation similar to ferumoxtran 10 was approved for iron replacement therapy. Like ferumoxtran 10, this compound is taken up by normal lymph nodes and excluded from malignant nodal tissue.
* Results of a recent National Cancer Institute (NCI) trial (11-C-0098) in 15 patients revealed that using the dose of 7.5 mg/kg Fe is safe and yields homogenous and accurate signal changes in benign lymph nodes in comparison with the 4 and 6 mg/kg Fe doses. This dose was further tested in 5 patient's with known or suspected nodal involvement from prostate cancer and in four of five patients positive lymph nodes had a lower signal drop than the benign nodes. The one case in which there was uptake by positive nodes may have been on a vascular basis. This pilot study stimulated interest in a larger study involving a variety of cancer types.

Primary Objective:

-To compare the difference in signal between metastatic and normal nodes in prostate, kidney and bladder cancer patients.

Eligibility

* Subject must be greater than or equal to 18 years old.
* Eastern Cooperative Oncology Group Performance score of 0 to 2.
* There are 3 parallel arms in this study. All patients must have evidence of lymph node involvement (with a short axis diameter greater than or equal to 1.5 cm).
* In addition:
* Arm 1: Subject must have a documented diagnosis of prostate cancer.
* Arm 2: Subject must have a documented diagnosis of bladder cancer (transitional cell carcinoma).
* Arm 3: Subject must have a documented diagnosis of kidney cancer (all renal cell cancer types).

Design:

* This is a single site 3-arm (arm 1=prostate cancer, arm 2=bladder cancer, arm 3=kidney cancer) study enrolling 50 evaluable patients (30 evaluable in each arm 1, 10 evaluable in arms 2 and 3) with documented prostate, bladder or kidney cancer with evidence of lymph node involvement \[with a size of greater than or equal to 1.5 cm measured on conventional imaging (e.g. CT, MRI)\].
* All subjects will undergo pre-infusion, 24, 48 hours post-Ferumoxytol infusion (dose of 7.5mg/kg Fe) MRI consisting of T1 weighted (W), T2W and T2\*W 3 Tesla MRI.
* Imaging will be correlated with histology of resected or biopsied lymph nodes when available. Occasionally, patients may not undergo biopsy or surgical excision of their lymph nodes. This may occur if their lymph nodes are overtly large and therefore highly likely to represent lymph node involvement. In such cases, patients will be evaluated with clinical follow up which typically occurs every three months in most NCI protocols. If the lesion demonstrates growth or regression based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria on these follow up studies' then the lesion will be considered positive for tumor. If it is stable for at least one year, then it will be considered non-malignant. The MR imaging analysis will be intra-patient.
* Patients will also undergo ultrasound examination of imageable lymph nodes (e.g. inguinal nodes) at pre-infusion and 24, 48 hours post-Ferumoxytol infusion time points. The signal changes at post-infusion ultrasound will be visually evaluated to determine if the uptake of ferumoxytol alters sonographic features.

Arms:
arm 1: Ferumoxytol +MRI

Interventions: intervention 1: Ferumoxytol intervention 2: Magnetic Resonance Imaging (MRI)
Intervention descriptions: intervention 1: 7.5mg/kg intravenous (IV) infusion intervention 2: 3 MRIs: pre-infusion, 24 and 48 hours post-infusion

Protocol document:
Prot_SAP_000.pdf: 
Abbreviated Title: Ferumoxytol MRI in GU Cancers 
Version Date: 12-20-2016 
Amendment Letter: D 
NCI Protocol #: 
14-C-0107 
Abbreviated Name: Ferumoxytol MRI in GU Cancers 
TITLE:  Evaluation of Ferumoxytol Enhanced MRI for the Detection of Lymph Node 
Metastases in Genitourinary (Prostate, Bladder and Kidney) Cancers 
Principal Investigator: Baris Turkbey, M.D.,MIP/CCR/NCI A-F 
 
 
 
 
 
Building 10, Room B3B69 
 
 
 
 
 
Bethesda, MD 20892 
 
 
 
 
 
Tel: 240-760-6112  
 
 
 
 
 
turkbeyi@mail.nih.gov  
 
 
 
Lead Associate Investigator: Peter L. Choyke, M.D., MIP/CCR/NCI A-F 
Associate Investigators: Peter A. Pinto, M.D., UOB/CCR/NCI A-F 
  
 
 
 
 
W. Marston, Linehan M.D., UOB/CCR/NCI A,B,E 
 
 
 
 
 
Piyush Agarwal M.D., UOB/CCR/NCI A,B,E 
  
 
 
 
 
Ravi Madan, M.D., GMB/ CCR/NCI A,B,E 
 
 
 
 
 
James Gulley, M.D., Ph.D., GMB/CCR/NCI A,B,E 
 
 
 
 
 
Andrea B. Apolo, M.D., GMB/CCR/NCI A,B,E 
 
 
 
 
 
Adam R. Metwalli, M.D., UOB/CCR/NCI A,B,E 
 
 
 
 
 
Deborah E. Citrin, M.D.,ROB/CCR/NCI A,B,E 
  
 
 
 
 
William Dahut, M.D., GMB/CCR/NCI A,B,E 
 
 
 
 
 
Bradford J. Wood M.D., Center for Interventional Oncology/CC A,B,E,F 
 
  
 
 
 
Maria Merino, M.D., LP/CCR/NCI E,F 
 
 
 
 
 
Paula Jacobs PhD., CIP/DCTD/NCI F 
Yolanda McKinney, R.N., OCD/CCR/NCI A,B,C 
  
 
 
            Liza Lindenberg, MD, MIP/CCR/NCI A-F 
 
 
 
 
 
 
  
Statistician:  
 
 
Joanna H. Shih, Ph.D., BRB/ DCTD/NCI F 
Referral Contact/ 
Yolanda McKinney, RN, OCD/CCR/NCI A,B,C 
Study Coordinator:  
Building 10 Room B3B69 
 
 
 
 
 
Bethesda, MD 20892 
 
 
 
 
 
Tel: 240-760-6095  
 
 
 
 
 
ymckinney@mail.nih.gov  
 
 
 
 


Abbreviated Title: Ferumoxytol MRI in GU Cancers 
Version Date: 12-20-2016 
2 
 
Roles   
A. Obtain information by intervening or interacting with 
living individuals for research purposes 
B. Obtaining identifiable private information about 
living individuals 
C. Obtaining the voluntary informed consent of 
individuals to be subjects 
D. Makes decisions about subject eligibility 
E. Studying, interpreting, or analyzing identifiable 
private information or data/specimens for research 
purposes 
F. Studying, interpreting, or analyzing de-identified data 
or specimens for research purposes 
G. Some/all research activities performed outside NIH 
Commercial Agents:  Ferumoxytol 
 
 


Abbreviated Title: Ferumoxytol MRI in GU Cancers 
Version Date: 12-20-2016 
3 
 
 
PRECIS 
Background: 
• Conventional imaging modalities (e.g. computed tomography [CT] and magnetic 
resonance imaging [MRI]) are currently used for the detection of lymph node 
metastases in many cancer types, including prostate, bladder and kidney cancers, 
however diagnosis is based on node enlargement which is neither sensitive nor 
specific (i.e. small nodes harbor metastases, large nodes can be hyperplastic). 
• As a consequence, the standard of care is to remove numerous lymph nodes during 
surgery or to biopsy enlarged nodes to ascertain lymph node status. 
• In 2003 Dextran coated ultra small superparamagnetic iron oxide particles (USPIO), 
also known as Ferumoxtran-10 (Combidex®, AMAG Pharmaceuticals, Inc. 
Lexington, MA, US) was shown to localize lymph node metastases with much greater 
accuracy than unenhanced MRI. Although a large study in prostate cancer was 
successful, an FDA Advisory Panel did not recommend approval and the company 
abandoned the agent 
• In 2009 Ferumoxytol (Feraheme® AMAG Pharmaceuticals, Inc. Lexington, MA, 
US) a semi-synthetic carbohydrate coated, magnetic iron oxide preparation similar to 
ferumoxtran 10 was approved for iron replacement therapy.  Like ferumoxtran 10, 
this compound is taken up by normal lymph nodes and excluded from malignant 
nodal tissue.  
• Results of a recent NCI trial (11-C-0098) in 15 patients revealed that using the dose 
of 7.5 mg/kg Fe is safe and yields homogenous and accurate signal changes in benign 
lymph nodes in comparison with the 4 and 6 mg/kg Fe doses. This dose was further 
tested in 5 patients with known or suspected nodal involvement from prostate cancer 
and in four of five patients positive lymph nodes had a lower signal drop than the 
benign nodes.  The one case in which there was uptake by positive nodes may have 
been on a vascular basis.  This pilot study stimulated interest in a larger study 
involving a variety of cancer types. 
Primary Objective 
• To compare the difference in signal between metastatic and normal nodes in prostate, 
kidney and bladder cancer patients. 
Eligibility 
• Subject must be ≥18 years old. 
• Eastern Cooperative Oncology Group Performance score of 0 to 2. 
• There are 3 parallel arms in this study.  All patients must have evidence of lymph 
node involvement (with a short axis diameter ≥1.5cm).  
• In addition:  
o Arm 1: Subject must have a documented diagnosis of prostate cancer, 
o Arm 2: Subject must have a documented diagnosis of bladder cancer 
(transitional cell carcinoma) 
o Arm 3: Subject must have a documented diagnosis of kidney cancer (all 
renal cell cancer types)  


Abbreviated Title: Ferumoxytol MRI in GU Cancers 
Version Date: 12-20-2016 
4 
 
Design: 
• This is a single site 3-arm (arm 1=prostate cancer, arm 2=bladder cancer, arm 3=kidney 
cancer) study enrolling 50 evaluable patients (30 evaluable in arm 1, 10 evaluable in arms 
2 and 3) with documented prostate, bladder or kidney cancer with evidence of lymph 
node involvement [with a size of ≥1.5cm measured on conventional imaging (e.g. CT, 
MRI)]. 
• All subjects will undergo pre-infusion, 24, 48 hours post-Ferumoxytol infusion (dose of 
7.5mg/kg Fe) MRI consisting of T1 weighted (W), T2W and T2*W 3 Tesla MRI.  
• Imaging will be correlated with histology of resected or biopsied lymph nodes when 
available. Occasionally, patients may not undergo biopsy or surgical excision of their 
lymph nodes. This may occur if their lymph nodes are overtly large and therefore highly 
likely to represent lymph node involvement. In such cases, patients will be evaluated with 
clinical follow up which typically occurs every three months in most NCI protocols.  If 
the lesion demonstrates growth or regression based on RECIST 1.1 criteria on these 
follow up studies then the lesion will be considered positive for tumor.  If it is stable for 
at least one year then it will be considered non-malignant.  The MR imaging analysis will 
be intra-patient. 
• Patients will also undergo ultrasound examination of imageable lymph nodes (e.g. 
inguinal nodes) at pre-infusion and 24, 48 hours post-Ferumoxytol infusion time points. 
The signal changes at post-infusion ultrasound will be visually evaluated to determine if 
the uptake of ferumoxytol alters sonographic features. 
 
STUDY SCHEMA 
 


Abbreviated Title: Ferumoxytol MRI in GU Cancers 
Version Date: 12-20-2016 
5 
 
TABLE OF CONTENTS 
PRECIS ........................................................................................................................................... 3 
TABLE OF CONTENTS ................................................................................................................ 5 
1 
INTRODUCTION ................................................................................................................... 7 
1.1 
Study Objectives ............................................................................................................. 7 
1.2 
Background and Rationale .............................................................................................. 7 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ....................................................... 17 
2.1 
Eligibility Criteria ......................................................................................................... 17 
2.2 
Screening Evaluation .................................................................................................... 18 
2.3 
Registration Procedures ................................................................................................ 19 
3 
STUDY IMPLEMENTATION ............................................................................................. 19 
3.1 
Study Design ................................................................................................................. 19 
3.2 
Ferumoxytol Administration ......................................................................................... 20 
3.3 
MRI scan ....................................................................................................................... 20 
3.4 
Ultrasound ..................................................................................................................... 21 
3.5 
Procedure Monitoring ................................................................................................... 21 
3.6 
Duration of Follow Up .................................................................................................. 21 
3.7 
Study Calendar .............................................................................................................. 22 
3.8 
Surgical Guidelines ....................................................................................................... 23 
3.9 
Criteria for Removal from Study .................................................................................. 23 
3.10 
Supportive Care Guidelines .......................................................................................... 24 
4 
DATA COLLECTION AND EVALUATION ..................................................................... 24 
4.1 
Data Collection ............................................................................................................. 24 
4.2 
Toxicity Criteria ............................................................................................................ 24 
4.3 
Imaging Interpretation .................................................................................................. 25 
4.4 
Pathology and Imaging Correlation .............................................................................. 25 
5 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
 
25 
5.1 
Definitions..................................................................................................................... 25 
5.2 
NCI-IRB and NCI Clinical Director (CD) Reporting ................................................... 27 
5.3 
Data and Safety Monitoring Plan .................................................................................. 28 
6 
STATISTICAL CONSIDERATIONS .................................................................................. 28 
6.1 
Study Design/Endpoints................................................................................................ 28 


Abbreviated Title: Ferumoxytol MRI in GU Cancers 
Version Date: 12-20-2016 
6 
 
6.2 
Sample Size/Accrual Rate ............................................................................................. 28 
6.3 
Stratification Factors ..................................................................................................... 28 
6.4 
Analysis of Primary Endpoint ....................................................................................... 29 
6.5 
Analysis of Secondary Endpoints ................................................................................. 29 
7 
PHARMACEUTICAL INFORMATION ............................................................................. 30 
7.1 
Ferumoxytol .................................................................................................................. 30 
8 
HUMAN SUBJECTS PROTECTIONS ................................................................................ 31 
8.1 
Rationale For Subject Selection .................................................................................... 31 
8.2 
Participation of Children ............................................................................................... 31 
8.3 
Participation of Subjects Unable to Give Consent ........................................................ 31 
8.4 
Evaluation of Benefits and Risks/Discomforts ............................................................. 31 
8.5 
Consent and Assent Process and Documentation ......................................................... 32 
9 
REFERENCES ...................................................................................................................... 34 
10 
Appendices ........................................................................................................................ 38 
10.1 
APPENDIX A: EXCERPT FROM FERUMOXYTOL PACKAGE INSERT [4] ....... 38 
10.2 
APPENDIX B: Performance Status Criteria................................................................. 40 


Abbreviated Title: Ferumoxytol MRI in GU Cancers 
Version Date: 12-20-2016 
7 
 
1 
INTRODUCTION 
1.1 
Study Objectives 
1.1.1 Primary Objective 
1.1.1.1 To compare the difference in signal between metastatic and normal nodes in prostate, 
kidney and bladder cancer patients. 
1.1.2 Secondary Objectives 
1.1.2.1 To determine the most optimal timing for imaging: 24 hours vs. 48 hours post infusion 
1.1.2.2 To determine the difference in signal within metastatic nodes in prostate, kidney, 
bladder cancer patients at ultrasonography. 
1.2 
Background and Rationale 
1.2.1 Ferumoxytol 
Ferumoxytol (FeraHeme®, AMAG Pharmaceuticals, Inc, Lexington, MA) is a semi-synthetic 
carbohydrate coated magnetic iron oxide preparation indicated for iron replacement therapy 
specifically in patients with chronic renal disease.  It is administered as a bolus and has minimal 
immunologic reactions. The safety profile of Ferumoxytol in Phase 1-3 clinical trials is excellent 
[1, 2]. 
Because of its magnetic properties it has been proposed as an MR imaging agent. Li et al 
evaluated the feasibility of first-pass contrast enhanced MR angiography using Ferumoxytol in 
11 patients and reported satisfactory arterial enhancement with diluted Ferumoxytol [3].  The 
same group prospectively evaluated the utility of Ferumoxytol enhanced MRI for the diagnosis 
of deep venous thrombosis in 9 patients and compared Ferumoxytol enhanced scans with pre-
contrast time-of-flight MR images and reported that Ferumoxytol enhanced MRI depicted deep 
venous thrombosis with higher contrast-noise-ratios than conventional non-contrast enhanced 
methods [4].  Neuwelt et al studied the optimum time of delayed contrast enhancement of 
Ferumoxytol and compared its enhancement with that of gadolinium chelates in 12 patients with 
malignant brain tumors.  They reported a maximal Ferumoxytol enhancement at 24 to 28 hours 
after Ferumoxytol injection and concluded that Ferumoxytol stays intravascular in the early 
phase after injection, making it potentially useful to measure tumor perfusion.  The injected 
doses were 1mg/kg Fe and 1.5mg/kg Fe, no adverse effects were reported in this trial [5].  
Ultrasmall particles of iron oxide (USPIOs) such as Ferumoxytol are known to be taken up by 
macrophages within lymph nodes, thus providing an impetus to study them as lymph node 
imaging agents.   There is limited clinical experience with Ferumoxytol enhanced MR imaging 
for metastatic lymph node mapping.  Harisinghani et al. reported using Ferumoxytol in 
determining the magnitude of nodal MRI signal changes in 10 prostate cancer patients, who had 
26 nodes of which 20 were benign.  Ferumoxytol was injected at a dose of 4mg Fe/kg at a rate of 
2ml/seconds.  MR imaging was performed before, and 5, 18 and 24 hours following the 
Ferumoxytol injection.  A significant drop in the signal-to-noise ratio (SNR) was shown in 
benign nodes, whereas little change in SNR was noted within malignant nodes.  Maximum 
contrast was detected at scans obtained 24 hours after injection but trend curves suggested better 
results might be seen at later time points.  No adverse effects were observed in enrolled patients 
[6]. 
See APPENDIX A: EXCERPT FROM FERUMOXYTOL PACKAGE INSERT [4]


Abbreviated Title: Ferumoxytol MRI in GU Cancers 
Version Date: 12-20-2016 
8 
 
2 
APPENDICES 
APPENDIX A for pharmaceutical details. 
2.1.1.1 Pharmacology and Toxicology 
Ferumoxytol is a non-stoichiometric magnetite (superparamagnetic iron oxide) coated with 
polyglucose sorbitol carboxymethylether.  The overall colloidal particle size is 17-31 nm in 
diameter.  The chemical formula of Ferumoxytol is Fe5874O8752-C11719H18682O9933Na414 with an 
apparent molecular weight of 750 kDa.  
Ferumoxytol injection is an aqueous colloidal product that is formulated with mannitol. It is a 
black to reddish brown liquid, and is provided in single use vials containing 510 mg of elemental 
iron.  Each mL of the sterile colloidal solution of Ferumoxytol injection contains 30 mg of 
elemental iron and 44 mg of mannitol, and has low bleomycin-detectable iron.  The formulation 
is isotonic with an osmolality of 270-330 mOsm/kg.  The product contains no preservatives, and 
has a pH of 6 to 8 [7]. 
Ferumoxytol consists of a superparamagnetic iron oxide core that is coated with a carbohydrate 
shell, which helps to isolate the bioactive iron from plasma components until the iron-
carbohydrate complex enters the reticuloendothelial system macrophages of the liver, spleen and 
bone marrow.  The iron is released from the iron-carbohydrate complex within vesicles in the 
macrophages.  Iron then either enters the intracellular storage iron pool (e.g., ferritin) or is 
transferred to plasma transferrin for transport to erythroid precursor cells for incorporation into 
hemoglobin. 
The pharmacokinetic (PK) behavior of Ferumoxytol has been examined in healthy subjects and 
in patients with chronic kidney disease on hemodialysis. Ferumoxytol exhibited dose-dependent, 
capacity-limited elimination from plasma with a half life of approximately 15 hours in humans. 
The clearance was decreased by increasing the dose of Ferumoxytol. Volume of distribution was 
consistent with plasma volume, and the mean maximum observed plasma concentration (Cmax) 
and terminal half-life (t1/2) values increased with dose. The estimated values of CL and Vd 
following two 510 mg doses of Ferumoxytol administered intravenously within 24 hours were 
69.1 mL/hr and 3.16 L, respectively. The Cmax and time of maximum concentration (tmax) were 
206 mcg/mL and 0.32 hr, respectively. Rate of infusion had no influence on Ferumoxytol PK 
parameters. No gender differences in Ferumoxytol PK parameters were observed. Ferumoxytol 
is not removed by hemodialysis [7]. 
The safety profile of Ferumoxytol has been assessed in clinical trials including both MR imaging 
and iron replacement therapy [1-4, 6].  In a randomized double-blind, ascending dose 
pharmacokinetic study of 61 subjects (41 healthy volunteers and 20 hemodialysis patients), 6 
healthy subjects received placebo, 24 subjects received 1 (n=8), 2 (n=8) or 4 (n=8) mg/kg Fe 
dose injected at 60mg Fe/min, whereas the remainder 11 subjects received 4mg Fe/kg at 
injection rates of 90 (n=3), 180 (n=3) or 1800 (n=5) mg Fe/min.  Twenty hemodialysis subjects 
received 125 (mean dose of 1.5+/-0.2/kg) (n=10) or 250 (mean dose of 3.2+/-0.6/kg) (n=10) mg 
Fe over 5 minutes. The blood half life of Ferumoxytol was 9.3 hours and it was increased to 14.5 
hours in normal subjects with increasing dose, moreover the half life was similar for the 
hemodialysis patient group.  Among normal subjects, no consistent, clinically relevant or 
unexpected changes were observed; only one adverse effect, which was metallic taste, was 
encountered in one subject.  For the hemodialysis patient group, no serious adverse events, no 


Abbreviated Title: Ferumoxytol MRI in GU Cancers 
Version Date: 12-20-2016 
9 
 
episodes of hypersensitivity or anaphylaxis and no episodes of hypotension were observed after 
Ferumoxytol injection.  Reported minor adverse events included nausea and vomiting in 1 
patient after injection [1]. 
In a randomized clinical trial including 21 adult anemic chronic kidney disease patients, 10 
patients received 4 intravenous doses Ferumoxytol at 255 mg Fe given every 2-3 days, 11 
patients received 2 intravenous doses of Ferumoxytol at 510 mg Fe given 1 week apart.  A total 
of 7 non-serious adverse effects were recorded in 5 patients, the adverse events included solitary 
instances of mild constipation a day after injection, mild chills an hour after dosing, mild tingling 
a day after dosing, moderate gastrointestinal upset of presumed viral etiology a day after dosing, 
mild delayed pruritic, erythematous rash 3 days after dosing, and mild pain at the injection site 
that resolved after reinsertion of the intravenous line in a different site [2]. 
In imaging clinical trials [3, 4, 6], all of which were done with lower doses administered than 
done in iron replacement trials, no serious adverse effects were observed except in one patient, 
who had urgent diarrhea 1.5 hours after injection [3]. 
FDA has also announced a drug safety communication for ferumoxytol with strengthened 
warnings and changed prescribing instructions and among one of the recommendations stated 
that ferumoxytol should be administrated diluted as an IV infusion over a minimum of 15 
minutes but not as an undiluted IV injection. 
(http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProduc
ts/ucm440479.htm). 
2.1.1.2 Ferumoxytol Enhanced MR imaging for Lymph node mapping 
There is limited clinical experience with Ferumoxytol enhanced MR imaging for metastatic 
lymph node mapping.  Harisinghani et al. reported using Ferumoxytol in determining the 
magnitude of nodal MRI signal changes in 10 prostate cancer patients, who had 26 nodes of 
which 20 were benign with a mean short axis diameter of 6mm and 6 were malignant with a 
mean short axis diameter of 7mm.  Ferumoxytol was injected at a dose of 4mg Fe/kg at a rate of 
2ml/seconds.  MR imaging was performed before, at 5, 18 and 24 hours following the 
Ferumoxytol injection.  A significant drop in the signal-to-noise ratio (SNR) was shown in 
benign nodes, whereas little change in SNR was noted within malignant nodes.  Maximum 
contrast was detected at scans obtained 24 hours after injection but trend curves suggested better 
results might be seen at later time points.  No adverse effects were observed in enrolled patients 
[6]. 
2.1.2 Study Diseases  
2.1.2.1 Metastatic Lymph Node involvement in Prostate Cancer 
Prostate cancer is the second most common cause of cancer death in men in the United States.  
The American Cancer Society estimates that there were 238,590 new cases of prostate cancer 
and 29,720 deaths due to prostate cancer in the United States in 2013 [8].  Approximately 17% 
of American men will receive the diagnosis of prostate cancer during their lifetime and 20% of 
these men will die of the disease [9]. Accurate lymph node staging is important for treatment 
planning in prostate cancer, and its implication on prognosis is well established [10-12]. 
However, extended pelvic node dissection represents a technically more challenging surgery and 
may be associated with higher complication rates (i.e. lymphocele, deep venous thrombosis, 
pelvic hematoma, fever, urinary retention etc.) that may result in longer hospital stays [13]. 


Abbreviated Title: Ferumoxytol MRI in GU Cancers 
Version Date: 12-20-2016 
10 
 
Therefore, a reliable pre-operative imaging method demonstrating metastatic involvement of 
lymph nodes can potentially render unnecessary, a formal lymph node dissection. 
2.1.2.2 Metastatic Lymph Node Involvement in Bladder Cancer 
Bladder cancer is the most common malignancy of the urinary system and is four times more 
common in women than in men [14]. The American Cancer Society estimates that there were 
72,570 new cases of bladder cancer and 15,210 deaths due to bladder cancer in the United States 
in 2013 [8]. Radical cystectomy, which involves removal of the bladder and regional lymph 
nodes, is the mainstay of treatment for muscle-invasive bladder cancer. In patients who undergo 
radical cystectomy, the extent of pelvic lymph node dissection is an important predictor of 
survival in those with both positive and negative lymph nodes [15-18]. Lymph node dissection 
guides further treatment recommendations by improving regional disease control and pathologic 
nodal staging while also detecting and removing metastatic lymph nodes, thus offering a direct 
therapeutic benefit. However, the lack of standardized lymphadenectomy procedures among 
institutions prevents consensus on what determines an adequate lymph node dissection at the 
time of radical cystectomy. There is a significant need for better imaging methods to detect 
lymph node metastases in bladder cancer patients to improve the completeness of lymph node 
removal. By identifying metastatic lymph nodes before surgery, the use of pre-operative imaging 
may help establish standards for the anatomic extent of lymphadenectomy and improve 
oncologic outcomes. 
2.1.2.3 Metastatic Involvement in Kidney Cancer 
The role of lymph node dissection (LND) in conjunction with nephrectomy for locally advanced 
renal cell carcinoma (RCC) is controversial.  While there is no evidence of a benefit in low stage 
and organ confined, the available data for locally advanced and metastatic disease is conflicting.  
Lymph node involvement in RCC has been shown to be associated with larger tumors, higher 
grade tumors and locally advanced tumors [19].  Furthermore, most patients with positive lymph 
nodes also had distant metastases, although patients with both distant metastatic sites in 
conjunction with positive lymph nodes had markedly worse survival than those with either 
distant metastasis or regional lymph node metastasis [19].  Locoregional lymphadenectomy does 
not result in additional morbidity [19, 20].  Patients without lymph node metastasis demonstrate 
no benefit from LND [19, 20].  Conversely, others have demonstrated that long term durable 
survival can be achieved with retroperitoneal LND in patients with positive lymph nodes [19, 
21].  In addition, our group and others have shown previously that degree of lymph node 
involvement affects survival, with a greater percentage of patients with lower volume lymph 
node metastases surviving 5 years [22, 23].  
Crispen et al showed that nearly 40% of patients with high risk features will have lymph node 
metastases [24].  However, even with enlarged lymph nodes on standard preoperative imaging, 
fewer than half of patients with high risk tumors will be found to have pathological evidence of 
lymph node metastasis [25, 26].  More worrisome, a small percentage of patients with no 
evidence of lymph node involvement on preoperative imaging will be found with pathologic 
evidence of nodal disease at the time of surgery [20, 25].  Therefore it is clear that preoperative 
staging is inadequate to accurately detect lymph node involvement.  Based upon the 
preponderance of data available, lymph node dissection in the presence of small volume lymph 
node metastasis appears to be beneficial in terms of overall and cancer specific survival.  


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11 
 
Consequently, improvement in identification of lymph node involvement preoperatively is a 
clinical imperative.   
2.1.3 Rationale 
2.1.3.1 Conventional Methods for Imaging of Metastatic Lymph Node Involvement 
Currently available imaging modalities for detection of metastatic lymph node include computed 
tomography (CT) and magnetic resonance imaging (MRI), both of which rely primarily on size 
criteria for distinction of benign nodes from malignant ones. Using the size criteria for 
differentiating involved nodes from non-involved nodes can result in failure to detect metastases 
in small unenlarged nodes, whereas enlargement of a lymph node may be secondary to other 
pathologies such as hyperplasia, infection and inflammation [27, 28].  Thus, both false negative 
and false positive results are frequent. Reported sensitivity for CT and MRI for detection of 
lymph node metastases in prostate cancer varies between 24-78% and 27-69%, respectively 
depending on the mixture of advanced patients in the study group [29-33].  Hence, a method 
incorporating both anatomical and functional information for accurate imaging of metastatic 
lymph nodes is needed at the pretreatment stage of prostate cancer. 
2.1.3.2 Metastatic Lymph Node Imaging with Lymphotrophic nanoparticle MRI (LNMRI) 
Technique 
LNMRI is a recent technique for mapping metastatic lymph nodes which employs ultrasmall 
superparamagnetic iron oxide particles (USPIO) as contrast agents. Originally, USPIO particles 
[Ferumoxtran-10, Combidex® (Advanced Magnetics, Lexington, MA, USA), Sinerem® 
(Laboratorie Guerbet, Aulnay-sous-Bois, France)) were used in these studies.  Ferumoxtran-10 
particles range from 30 and 50nm in diameter and are composed of an iron oxide crystalline core 
measuring 4.3-6 nm and a covering material made up of low-molecular-weight dextran, which 
can pass through capillaries whereupon they are taken up by the reticuloendothelial system [34].  
For instance, a USPIO agent can localize within the normal lymph node either by direct 
transcapillary passage from the venules to the medullary sinuses or by extravasation across 
permeable capillary beds by a non-selective endothelial transcytosis allowing particles to drain 
into lymph nodes [35].  Regardless of how it arrives, within the normal lymph nodes, USPIO is 
internalized by macrophages thus causing accumulation within the node, which results in signal 
loss on MRI within normal areas of lymph nodes [36].  This accumulation of USPIO agents in 
benign lymph nodes causes a signal drop (negative contrast enhancement) in the T2* MR 
images, whereas lymph nodes completely or partially involved with metastatic cells retain their 
baseline signal characteristics [37]. 
LNMRI with a variety of USPIO agents has been reported to be useful in various cancer types 
including prostate, bladder, testicular, renal and rectum cancer.  Harisinghani et al. reported the 
utility of USPIO enhanced MRI in detection of small and undetectable lymph node metastases in 
33 prostate cancer patients using ferumoxtran 10 [38].  Heeskkers et al. examined the feasibility 
of USPIO (ferumoxtran-10) enhanced MRI and compared image quality of 1.5T and 3T systems 
in 48 patients with prostate cancer and concluded that 3T systems provide improved image 
quality and node border delineation [39].  Recently, the same group reported the utility of USPIO 
enhanced MRI for detection of lymph node metastases outside the area of routine pelvic lymph 
node dissection area in 41% of 58 prostate cancer patients [40]. 
Deserno et al. examined the role of USPIO enhanced MRI in the detection of lymph node 
metastases in 58 patients with bladder cancer and reported a sensitivity of 95% for USPIO 


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enhanced MRI, whereas the sensitivity for conventional MRI was 76% [41]. Harisinghani et al. 
evaluated feasibility of USPIO enhanced MRI for detecting metastatic disease within 
retroperitoneal nodes in 18 testicular cancer patients and reported sensitivity, specificity and 
accuracy as 88.2%, 92% and 90.4%, respectively [42].  Guimares et al. assessed USPIO 
enhanced MRI in identifying malignant nodal involvement in 9 renal cancer patients and 
reported sensitivity and specificity values of 100% and 95.7%, respectively [43].  Lahaye et al. 
determined diagnostic performance of predictive criteria for nodal staging with USPIO enhanced 
MRI in 28 rectal cancer patients and concluded that the estimated percentage of white region on 
USPIO enhanced T2* MRI, that corresponds to the portion of the lymph node involved with 
metastatic cells, can be used  as an index of  lymph node involvement [44]. Recently, Birkhauser 
et al. evaluated the diagnostic accuracy of combined USPIO (ferumoxtran-10) enhanced MRI 
and diffusion-weighted (DW MRI) in staging of normal-sized pelvic LNs in bladder and/or 
prostate cancer patients with 3-Tesla MRI. They imaged 75 patients 24–36 h after administration 
of ferumoxtran-10.  All patients were staged previously as N0 by conventional cross-sectional 
imaging. Combined USPIO-DW-MRI findings were analyzed by three independent readers and 
correlated with histopathologic LN findings after extended pelvic LN dissection and resection of 
primary tumors. Sensitivity and specificity for LN status of combined USPIO-DW-MRI versus 
histopathologic findings were evaluated on a per patient basis (primary end point) and per pelvic 
side (secondary end point). At histopathologic analysis, 2993 LNs (median: 39 LNs; range: 17–
68 LNs per patient) with 54 LN metastases (1.8%) were found in 20 of 75 (27%) patients. Per-
patient sensitivity and specificity for detection of LN metastases by the three readers ranged from 
65% to 75% and 93% to 96%, respectively; sensitivity and specificity per pelvic side ranged 
from 58% to 67% and 94% to 97%, respectively. A potential limitation was the absence of a 
node-to-node correlation of combined USPIO-DW-MRI and histopathologic analysis. They 
concluded that combined USPIO-DW-MRI improved detection of metastases in normal-sized 
pelvic LNs of bladder and/or prostate cancer patients [45]. 
USPIO enhanced MRI technique has practical difficulties and challenges, first is the need for 
performing pre and 24-36 hours post-contrast injection due to slow accumulation of the contrast 
within lymph nodes, which may diminish cost-effectiveness of this method.  Second is the 
intravenous infusion of ferumoxtran-10, which should be administered slowly through a filtered 
needle over a period of 15-30 minutes to minimize hypersensitivity-related side effects.  Finally, 
ferumoxtran-10 is currently not FDA approved and is unavailable both in the US and Europe.  
Therefore, although it was highly promising, Ferumoxtran-10 is simply unavailable.   
However, a similar agent, ferumoxytol (trade name FeraHeme), developed by the same company 
(AMAG Pharmaceuticals) was approved by the FDA in 2009 for iron replacement therapy. In 
this study, our primary objective will be to compare the difference in signal between metastatic 
and normal nodes in prostate, kidney and bladder cancer patients using intravenous ferumoxytol.  
2.1.4 Protocol 11-C-0098 Results 
Protocol 11-C-0098 was a dose ranging study in which the following doses of ferumoxytol were 
evaluated:  4mg/kg, 6mg/kg, 7.5mg/kg.  The results revealed that the dose of 7.5 mg/kg Fe was 
safe and yielded the best imaging results with more homogenous and reliable signal changes in 
benign lymph nodes in comparison with the 4 and 6 mg/kg Fe doses (Figure 1, Figure 2, Figure 
3, Figure 4). One patient out of 21 developed an allergic reaction after receiving approximately 
2.5mg/kg dose.  Patient had sneezing, redness in the face and the neck, he felt dizziness and hot. 
His mouth and throat became swollen. He had hives in his lips, left shoulder and nasal 


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congestion as well. He was assessed to have Grade 2 allergic reaction. He was discharged after a 
5 hour observation following resolving his symptoms. At 24 hour follow up, he reported no 
complaints. 
This study was conducted in patients undergoing surgery at NIH for localized prostate cancer 
where the incidence of prostate cancer lymph node metastases is realtively low.  Thus, the  utility 
of the agent  in depiction of signal change differences between benign and malignant lymph 
nodes could not be assessed.  Therefore, an additional five subjects with known or suspected 
lymph node metastases were added to validate the signal change differences between benign and 
malignant lymph nodes invaded with prostate cancer.  


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Figure 1:  Coronal T2* weighted MRI at the baseline scan demonstrates a right iliac chain lymph node, 24hr follow 
up scans after 4mg Fe/kg Ferumoxytol injection demonstrate a heterogeneous signal drop within the lymph node. 
 
Figure 2:  Coronal T2* weighted MRI at the baseline scan demonstrates a right iliac chain lymph node, 24 and 48 
hours follow up scans after 6mg Fe/kg Ferumoxytol injection demonstrate a heterogeneous signal drop within the 
lymph node. 


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Figure 3:  Axial T2* weighted MRI at the baseline scan demonstrates a bilateral iliac chain lymph nodes, 24hr 
follow up scan after 7.5mg Fe/kg Ferumoxytol injection demonstrate a homogeneous signal drop within the lymph 
node. 
 
Figure 4: Bar graphs show that the greatest signal drop was observed at 7.5mg Fe/kg dose in lymph nodes (LN), 
bone marrow right, left (BMR, BML). 


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In the 5 patients with suspected lymph node involvement (with a size of ≥1.5cm) ferumoxytol 
was injected (7.5mg Fe/kg) prior to imaging. Among 5 patients 4 patients had positive findings 
in their lymph nodes and the amount of signal drop was less in those suspicious lymph nodes 
than it was in the benign ones (Figure 5). However, there were some controversial findings in a 
small number of suspicious lymph nodes as a result of variable and heterogeneous signal changes 
after Ferumoxytol injection (Figure 6).  For instance, in one patient with obvious retroperitoneal 
lymphadenopathy there was uptake into the lymph nodes.  We believe this is on a vascular basis 
in which permeable angiogenic vessels in the nodes leaked ferumoxytol into the lymph node.  At 
histopathology, no normal lymphatic tissue was seen indicating the uptake was not due to 
macrophages but rather to leakage. 
MIP has two other MRI trials for prostate cancer, Protocols“13-C-0018” and “13-C-0145”. 
Protocol 13-C-0018, aims to evaluate feasibility of determining MR contrast enhancement 
differences in prostate cancers after Eovist injection. Protocol 13-C-0145, will not compete with 
this trial since patients previously enrolled on the 13-C-0145 study can still be eligible for the 
ferumoxytol trial. However, if a patient completes the current ferumoxytol protocol, he will not 
be eligible for the 13-C-0145 study since possibly retained iron particles will affect the accuracy 
of the Eovist enhanced MRI. 
 
Figure 5: Axial T2* weighted MRI at the baseline scan demonstrates a right internal iliac chain lymph node, 24hr 
follow up scan after 7.5mg Fe/kg Ferumoxytol injection demonstrate a homogeneous hyperintense signal within the 
lymph node, which is suspicious for malignant involvement. 


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Figure 6: Coronal T2* weighted MRI at the baseline scan demonstrates an enlarged right common iliac chain lymph 
node, 24hr follow up scan after 7.5mg Fe/kg Ferumoxytol injection demonstrate a heterogenous signal pattern with 
partial hyperintense focus within the lymph node, which is suspicious for partial malignant involvement. 
3 
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
3.1 
Eligibility Criteria 
3.1.1 Inclusion Criteria 
3.1.1.1 Subject must be ≥18 years old. 
3.1.1.2 Diagnosis 
• Arm 1: Subject must have a documented diagnosis of prostate cancer with 
evidence of lymph node involvement (with a short axis diameter of ≥1.5cm on a 
conventional CT or MRI obtained within 8 weeks of the Ferumoxytol imaging 
procedure) 
• Arm 2: Subject must have a documented diagnosis of bladder cancer (transitional 
cell carcinoma) with evidence of lymph node involvement (with a short axis 
diameter of ≥1.5cm on a conventional CT or MRI obtained within 8 weeks of the 
Ferumoxytol imaging procedure) 


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• Arm 3: Subject must have a documented diagnosis of kidney cancer (all renal cell 
cancer types) with evidence of lymph node involvement (with a short axis  
diameter of ≥1.5cm on a conventional CT or MRI obtained within 8 weeks of the 
Ferumoxytol imaging procedure) 
3.1.1.3 Subject must have Eastern Cooperative Oncology Group Performance score < 2. 
3.1.1.4 Ability to provide informed consent.  All subjects must sign an informed consent form 
indicating their understanding of the investigational nature and risks of the study before 
any protocol-related studies are performed. 
3.1.2 Exclusion Criteria 
3.1.2.1 Subjects with known hypersensitivity and allergy to iron 
3.1.2.2 Subjects with evidence of iron overload with a pre-study ferritin level greater than 370 
ng/ml and percent saturation of transferrin level greater than 40%.  Patients with lab 
values above these limits may be included in the study if documented hematology 
consultation rules out hemochromatosis, idiopathic or iatrogenic iron overload. 
3.1.2.3 Subjects with any coexisting medical or psychiatric condition that is likely to interfere 
with study procedures and/or results 
3.1.2.4 Subjects with severe claustrophobia unresponsive to oral anxiolytics 
3.1.2.5 Subjects with contraindications to MRI  
3.1.2.6 Subjects weighing >136 kg (weight limit for scanner table) 
3.1.2.7 Subjects with any type of pacemaker, cerebral aneurysm clips, shrapnel injury, or other 
implanted electronic devices or metal not compatible with MRI. 
3.1.2.8 Subjects with abnormal liver function tests suggesting liver dysfunction (AST and ALT 
>3 x of the upper limits of normal; total bilirubin >2 x the upper limits of normal or >3.0 
mg/dl in patients with Gilbert’s syndrome). 
3.1.2.9 Subjects with other medical conditions deemed by the principal investigator (or 
associates) to make the subject ineligible for protocol procedures. 
3.1.2.10 Women who are pregnant or breast-feeding. The effects of ferumoxytol on the 
developing human fetus are unknown.  For this reason, women of child-bearing 
potential and men must agree to use adequate contraception (hormonal or barrier 
method of birth control; abstinence) prior to study entry and for 1 day after study related 
imaging is completed.  Should a woman become pregnant or suspect she is pregnant 
while she or her partner is participating in this study, she should inform her treating 
physician immediately. 
3.1.3 Inclusion of Women and Minorities 
Members of all races and ethnic groups are eligible for this trial.  Women are excluded from arm 
1 of this trial as prostate cancer does not occur in females. 
3.2 
Screening Evaluation 
Subjects will be seen in the UOB, GMB or ROB clinics by members of each respective team. 
Conventional imaging (e.g. CT, MRI) confirming presence of prostate or bladder (transitional 
cell carcinoma) or kidney cancer (all types of renal cell cancer) with evidence of lymph node 
involvement [with a short axis diameter of ≥1.5cm measured on conventional CT or MRI] will 
be reviewed by Molecular Imaging Program Staff. 


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3.2.1 Screening Test 
3.2.1.1 Evaluations: 
• History 
• Weight 
• vital signs (BP, HR, RR, & Temperature) 
• clinical laboratory assessments (CBC w/diff, Acute Care Panel, Hepatic Panel, Mineral 
Panel, serum Iron, ferritin, % saturation transferrin and TIBC). 
• Serum or Urine Pregnancy Test in women of reproductive potential  
3.3 
Registration Procedures 
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent.  A registration Eligibility Checklist from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and sent via 
encrypted email to:  NCI Central Registration Office (HOIS) <ncicentralregistration-
l@mail.nih.gov>. After confirmation of eligibility at Central Registration Office, CRO staff will 
call pharmacy to advise them of the acceptance of the patient on the protocol prior to the release 
of any investigational agents.  Verification of Registration will be forwarded electronically via e-
mail to the research team. A recorder is available during non-working hours. 
4 
STUDY IMPLEMENTATION 
4.1 
Study Design 
This is an open label single site. The study will enroll 10 evaluable patients in each of the 3 study 
arms for a total of evaluable 30 patients. The 3 arms are: 
• Arm 1: Prostate Cancer, 
• Arm 2: Bladder Cancer (transitional cell carcinoma),  
• Arm 3: Kidney Cancer (all types of renal cell cancer). 
All subjects will undergo pre-infusion, 24, 48 hours post-Ferumoxytol infusion (dose of 
7.5mg/kg Fe) MRI consisting of T1 weighted (W), T2W and T2*W MRI in a 3 Tesla magnet. 
Additionally, all subjects will undergo pre-infusion, 24 hours, 48 hours post-Ferumoxytol 
infusion (dose of 7.5mg/kg Fe) ultrasound. Imaging will be correlated with histology of resected 
or biopsied lymph nodes when available or patient will be evaluated with clinical assessment and 
conventional imaging findings. Occasionally, patients may not undergo biopsy or surgical 
excision of their lymph nodes. This may occur if their lymph nodes are overtly large and 
therefore highly likely to represent lymph node involvement. In such cases, patients will be 
evaluated with clinical follow up which typically occurs every three months in most NCI 
protocols. 
An evaluable patient is defined as a patient who receives a dose of Ferumoxytol and receives the 
pre-infusion, 24 hour post-infusion and 48 hour post-infusion MRI and Ultrasound scans. 
Patients who do not undergo surgical excision or biopsy of the lymph nodes will be followed 
(per treatment protocol) for a minimum of 12 months. During this follow up, conventional 
images (e.g. CT, MRI) will be evaluated and RECIST 1.1 criteria will be used for assessment of 
metastatic involvement for correlation of Ferumoxytol enhanced MRI findings. According to 


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RECIST 1.1 criteria a lymph node is accepted as “pathologically enlarged” if its short axis 
diameter is ≥1.5cm on CT scan. During follow-up, lymph nodes identified as target lesions 
should always have the actual short axis measurement recorded. During follow up, at least a 30% 
decrease in size compared to the baseline, or a 20% increase in the short axis diameter compared 
to the baseline measurement will be considered as evidence of malignancy in the node. If the 
target lymph node demonstrates a decrease in size ≤ 30% or an increase in size ≤20% it will be 
determined to be stable and therefore likely to be non-malignant over a period of at least one 
year (Figure 7) [46].  
 
Figure 7: Example of the use of follow up studies. Baseline imaging demonstrates a lymph node with a short axis 
size of 1.1cm in presence of a serum PSA of 6.5ng/dl in a 72-year old S/P radical prostatectomy patient. 6 months 
follow up MRI after 3 cycles of hormone therapy demonstrates decrease of the lymph node size to 0.3cm 
accompanied with a PSA of 0.06ng/dl. The original lymph node would be considered malignant based on its 
shrinkage on appropriate therapy 
4.2 
Ferumoxytol Administration 
For all subjects in all three arms, ferumoxytol will be administered at a dose of 7.5mg/kg Fe.  
Each arm will include 10 evaluable patients.    
Ferumoxytol will be administered as an intravenous infusion in 50-200 mL 0.9% Sodium 
Chloride Injection, USP or 5% Dextrose Injection, USP over at least 15 minutes..   
4.3 
MRI scan 
Prior to entering the scanner the patient will answer the standard MRI safety checklist 
administered to all patients undergoing MRI in the Clinical Center to insure that it is safe to 
perform an MRI.  The patient will be placed into the magnet in supine position and an 
intravenous line will be placed.  A 32 channel cardiac coil will be used for MR imaging.  
The following scans will be obtained: 
• Scout view of the target lesion area to check positioning of the phased array cardiac 
coil. 
• Axial T1 weighted MRI of pelvis. 
• Axial T2 weighted MRI of pelvis. 
• Axial T2* weighted MRI of pelvis. 


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• Axial diffusion weighted MRI of the pelvis 
• Total nominal time: 40 minutes +/- 5 minutes for setup and clean-up +/- 10 minutes in 
case any sequence needs to be repeated due to unforeseen events such as patient 
motion during imaging acquisition.  At any given time the patient will be required to 
lie still for 5-7 minutes. 
After completion of the pre-infusion MRI scan, the patient will be taken into observation room 
and Ferumoxytol infusion will be performed as detailed above.  The patient will be released after 
determining vital signs are stable and requested to return for MR imaging at approximately 24 
and 48 hours later. 
24 hours following the Ferumoxytol infusion, the same MR imaging protocol specified above 
will be performed with the same MRI set up. 
48 hours following the Ferumoxytol infusion, the MR imaging protocol will again be performed 
with the same MRI set up. 
Following imaging acquisition, the data will be transferred to the clinical PACS system for 
storage. 
4.4 
Ultrasound 
Ultrasound images of the target lymph nodes will be obtained in accessible lymph nodes with 2 
different probes (9MHz and 6-15MHz probes) in the same session. Total nominal time for 
ultrasound imaging is expected to be 10-15 minutes. The same machine (GE LOGIQ E9) will be 
used for each scan and ultrasound will be performed by the same sonography technician to keep 
the imaging consistent. 
4.5 
Procedure Monitoring 
The Principal Investigator or other Licensed Independent Practitioner (individual who is licensed 
to practice independently, i.e. MD, NP, or PA) will be in attendance during infusion.  In the 
event of an emergency such as allergic reaction, emergent treatment will be initiated using 
emergency medication kits available in Molecular Imaging Clinic.  The attending from UOB, 
ROB, or GMB will be paged (301-496-1211) if needed to treat patient symptoms or for follow 
up care.  In the event the attending is unavailable, Dr. Turkbey should be called (240-760-6112). 
Vital signs: Blood pressure, heart rate, respiratory rate, will be taken prior to infusion and every 
15 minutes after infusion for 1 hour or until stable. Once stable, patient will be released from 
Molecular Imaging Clinic. 
4.6 
Duration of Follow Up 
Patients removed from study for unacceptable adverse events will be followed until the 
resolution or stabilization of the adverse event. 
Patients who will undergo biopsy or surgical intervention will remain on study until completion 
of their surgical procedure or biopsy (core needle biopsy or fine needle aspiration) and analysis 
of lymph node dissection, at which time they will be removed from study.   
Patients who do not undergo biopsy or surgical intervention will have their disease monitored per 
the protocol they are enrolled in.  If the target node is determined to be malignant based on >30% 
decreases or >20% increases in size then the patient will be removed from the study.  In cases 
when the target node does not change (≤30% decrease, ≤20% increase) then they will be 


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followed for at least one year.  The patient’s medical history and imaging studies will be 
acquired from the patient’s medical record, PACs, or their primary care MD. Thus, the patients 
will remain on study until such time as the nature of their target lymph node can be determined 
by follow up testing. 
In the event that a patient experiences an allergic reaction or toxicity greater than grade 2 during 
the Ferumoxytol infusion, the infusion will be stopped immediately and standard supportive 
measures instituted.  No further Ferumoxytol will be administered. 
4.7 
Study Calendar 
All efficacy and safety measurements obtained during the course of the study are summarized in 
the Study Calendar. 
Table 1: Study Calendar 
 
Pre-
study 
a,bUltrasound and MR imaging 
c, dSurgical 
procedure/ 
Core 
Needle/fine 
needle 
aspiration 
Biopsy 
cFollow up of 
medical 
history and 
conventional 
imaging 
studies 
 
 
Just 
prior 
to 
MRI 
Pre-
infusion 
MRI scan 
24 hour 
post 
infusion 
MRI scan 
48 hour 
post 
infusion 
MRI scan 
Within 12 weeks 
following 
Ferumoxytol 
enhanced MR 
imaging 
at least 1 year 
after 
Ferumoxytol 
infusion MRI 
Pathology report 
confirming 
prostate, bladder or 
kidney cancer 
X 
 
 
 
 
X 
 
Informed consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
CBC w/diff, plts 
X 
 
 
 
 
 
 
Serum chemistry 
X 
 
 
 
 
 
 
Serum Iron, 
ferritin, % 
saturation 
transferrin and 
TIBC 
X 
 
 
X 
 
 
 
Serum or Urine 
Pregnancy Test 
X 
Xe 
 
 
 
 
 
Intravenous line 
started 
 
X 
X 
 
 
 
 
Ferumoxytol 
infusion 
 
 
X 
 
 
 
 


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Pre-
study 
a,bUltrasound and MR imaging 
c, dSurgical 
procedure/ 
Core 
Needle/fine 
needle 
aspiration 
Biopsy 
cFollow up of 
medical 
history and 
conventional 
imaging 
studies 
 
 
Just 
prior 
to 
MRI 
Pre-
infusion 
MRI scan 
24 hour 
post 
infusion 
MRI scan 
48 hour 
post 
infusion 
MRI scan 
Within 12 weeks 
following 
Ferumoxytol 
enhanced MR 
imaging 
at least 1 year 
after 
Ferumoxytol 
infusion MRI 
Vital sign 
monitoring 
 
X 
X 
X 
X 
 
 
a: Ultrasound and MRI will be done on the same day. For the baseline (pre-infusion) time point, 
ultrasound will be done before the MRI and for post-infusion 24hr and 48hr time points the 
sequencing of these studies can change. 
b: Intravenous line starting, vital sign monitoring will be done after the MRI scans only, but not 
after the ultrasound scans. 
c: Imaging will be correlated with histology of resected or biopsied lymph nodes when available 
or patient will be evaluated with clinical assessment and conventional imaging findings (using 
RECIST criteria), which may be extended up to a period of at least 12 months in cases of stable 
nodes. 
d: Surgical excision or biopsy of the target lymph node will be performed within 12 weeks 
following the ferumoxytol enhanced MRI. 
e: Performed ≤ 48 hours prior to infusion of Ferumoxytol for all women of reproductive 
potential. The test need not be performed if screening test was done within appropriate time 
frame. 
4.8 
Surgical Guidelines 
As part of their standard of care for their cancer (prostate, bladder or kidney), subjects in each 
arm may have surgery or a biopsy of the lymph node within 12 weeks following Ferumoxytol 
enhanced MR imaging.  Pathologic specimens will be obtained for histological assessments. 
4.9 
Criteria for Removal from Study 
• If a patient is found to be pregnant after study enrollment but prior to Ferumoxytol 
infusion 
• Patients will be removed from study following prostatectomy or biopsy or after their 1 
year clinical assessment.  If the patient experiences an AE that prohibits them from 
completing the Ferumoxytol enhanced MR imaging session they will be taken off-study 
upon resolution of toxicity.  In cases where Ferumoxytol enhanced MR imaging findings 
indicate possible loco-regional and/or distant metastases, the information will be 
discussed with the referring physician.  Further evaluation with standard of care 
diagnostic imaging and/or biopsy will be performed at the discretion of the referring 
physician.  The surgical excision or biopsy will be performed only if it is clinically 


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indicated (standard of care).  As the significance of a Ferumoxytol enhanced MR 
imaging-depicted lesion is uncertain, the decision to pursue pathological confirmation 
and the methods of doing so will be left to the referring clinician and is not dictated by 
this imaging protocol.   
• A patient may withdraw from the study at any time.  
4.9.1 Off-Study Procedure 
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off-
study. An off-study form from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be completed and 
sent via encrypted email to:  NCI Central Registration Office (HOIS) <ncicentralregistration-
l@mail.nih.gov>. 
4.10 Supportive Care Guidelines 
In the event that a subject has a reaction (allergic) to Ferumoxytol, all appropriate medical 
measures will be taken immediately.  In rare instances, this may entail admission to the hospital 
on according to the directions from the referring team. 
5 
DATA COLLECTION AND EVALUATION 
5.1 
Data Collection  
Data will be collected by the Molecular Imaging Program staff and stored in a password-
protected file in NCI C3D.  The data will be entered at least on a weekly basis.  
Data collection will include demographics, the primary tumor diagnosis date, biopsy date, and 
pathological diagnosis including tumor grade. Monitoring for AEs will be performed from the 
start of Ferumoxytol infusion until 48 hours post infusion.  AEs related to the standard of care 
prostatectomy or needle biopsy will NOT be collected or reported under this protocol. Raw 
image data will be stored on a secure external drive.  Reconstructed imaging data will include 
storage of anonymized images from each time point and other extracted image parameters.  This 
will be stored in a secure, password protected imaging database.  Post-operative histology data 
and subsequent correlative analysis will be stored in the password-protected database. 
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breech in our plan to protect 
subject confidentiality and trial data has occurred, the IRB will be notified.  
 
5.2 
Toxicity Criteria 
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study.  The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40).  


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5.3 
Imaging Interpretation 
The location of lymph nodes will be indicated on T1W, T2W and T2*W unenhanced MR images 
and the size of each node will be measured from the T1 images.  Each visualized node will be 
assigned a number and a site (e.g. right, left, internal, external iliac, right left retroperitoneal).  
The location of the nodes will be transcribed to a map of the targeted region (chest, abdomen or 
pelvis).  The map, nodal characterizations, and the MR images will be made available to the 
referring physician for reference.  Signal intensity of visualized target lymph node will be 
recorded on unenhanced and 24 and 48 hours post Ferumoxytol infusion T2*W MR images by 
placing operator defined region-of-interest.  Signal intensity changes will be measured between 
pre-infusion, 24 and 48 hours post Ferumoxytol infusion MR scans. 
For the ultrasound imaging interpretation, the baseline and 24hour, 48hour post-infusion 
ultrasound images will be visually compared to monitor the signal changes. 
5.4 
Pathology and Imaging Correlation 
As part of standard care, lymph nodes mapped on MR imaging may be resected during at the 
time of surgery or may be biopsied via core needle technique or fine needle aspiration.  Resected 
nodes will be named and numbered based on their location in diagrammatic maps obtained from 
MR images.  Multiple sections of resected or biopsied lymph nodes will be stained with 
hemotoxylin and eosin and the slides will be reviewed by NCI pathologists.  The histopathology 
results will be compared with signal intensity change amounts between unenhanced, 24 and 48 
hours post Ferumoxytol infusion T2*W MR images.  No samples will be obtained or stored on 
this protocol other than in the Pathology Department, NCI, NIH. 
Patients who do not undergo surgical excision or biopsy of the lymph nodes will be followed 
(per treatment protocol) for a minimum of 12 months. During this follow up, conventional 
images (e.g. CT, MRI) will be evaluated and RECIST 1.1 criteria will be used for assessment of 
metastatic involvement for correlation of Ferumoxytol enhanced MRI findings. 
6 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN 
6.1 
Definitions 
6.1.1 Adverse Event 
An adverse event is defined as any reaction, side effect, or untoward event that occurs during the 
course of the clinical trial associated with the use of a drug in humans, whether or not the event 
is considered related to the treatment or clinically significant. For this study, AEs will include 
events reported by the patient, as well as clinically significant abnormal findings on physical 
examination or laboratory evaluation. A new illness, symptom, sign or clinically significant 
laboratory abnormality or worsening of a pre-existing condition or abnormality is considered an 
AE.  All AEs must be recorded on the AE case report form unless otherwise noted above in 
Section 5.1. 
All AEs, including clinically significant abnormal findings on laboratory evaluations, regardless 
of severity, will be followed for 48 hours after dose infusion. AEs should be reported up to 30 
days following the last dose of study drug.   


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6.1.2 Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
6.1.3 Unexpected adverse reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been observed; or, 
if an investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. 
"Unexpected”, also refers to adverse events or suspected adverse reactions that are mentioned in 
the investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation. 
6.1.4 Serious  
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious 
Adverse Event or if it compromises the safety, welfare or rights of subjects or others. 
6.1.5 Serious Adverse Event 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
• 
Death, 
• 
A life-threatening adverse drug experience 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect. 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
6.1.6 Disability 
A substantial disruption of a person’s ability to conduct normal life functions. 
6.1.7 Life-threatening adverse drug experience 
Any adverse event or suspected adverse reaction that places the patient or subject, in the view of 
the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction that had it occurred in a more severe form, might have caused death. 


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6.1.8 Protocol Deviation (NIH Definition) 
Any change, divergence, or departure from the IRB-approved research protocol. 
6.1.9 Non-compliance (NIH Definition) 
The failure to comply with applicable NIH Human Research Protections Program (HRPP) 
policies, IRB requirements, or regulatory requirements for the protection of human research 
subjects.  
6.1.10 Unanticipated Problem 
Any incident, experience, or outcome that: 
•  Is unexpected in terms of nature, severity, or frequency in relation to  
(a) the research risks that are described in the IRB-approved research protocol and informed 
consent document; Investigator’s Brochure or other study documents, and 
(b) the characteristics of the subject population being studied; AND 
• Is related or possibly related to participation in the research; AND 
• Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
6.2 
NCI-IRB and NCI Clinical Director (CD) Reporting 
6.2.1 NCI-IRB and NCI CD Expedited Reporting of Unanticipated Problems and Deaths 
The Protocol PI will report in the NIH Problem Form to the NCI-IRB and NCI Clinical Director: 
• All deaths, except deaths due to progressive disease  
• All Protocol Deviations 
• All Unanticipated Problems 
• All non-compliance 
Reports must be received within 7 days of PI awareness via iRIS. 
6.2.2 NCI-IRB Requirements for PI Reporting of Adverse Events at Continuing Review 
1. A summary of all protocol deviations in a tabular format to include the date the deviation 
occurred, a brief description of the deviation and any corrective action. 
2. A summary of any instances of non-compliance 
3. A tabular summary of the following adverse events: 
• All Grade 2 unexpected events that are possibly, probably or definitely related to the 
research;  
• All Grade 3 and 4 events that are possibly, probably or definitely related to the 
research;  
• All Grade 5 events regardless of attribution;  
• All Serious Events regardless of attribution.  


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28 
 
NOTE: Grade 1 events are not required to be reported.  
6.3 
Data and Safety Monitoring Plan 
6.3.1 Principal Investigator/Research Team  
This study will not have a formal data safety monitoring plan (DSMP), however, the Principal 
Investigator and Lead Associate Investigator will re-evaluate the protocol after each patient.  
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Adverse events will be reported as required above. Any safety concerns, 
new information that might affect either the ethical and or scientific conduct of the trial, or 
protocol deviations will be immediately reported to the IRB using iRIS.  
The principal investigator will review adverse event data on each patient to ensure safety and 
data accuracy. The principal investigator will personally conduct or supervise the investigation 
and provide appropriate delegation of responsibilities to other members of the research staff.  
7 
STATISTICAL CONSIDERATIONS 
7.1 
Study Design/Endpoints 
• This is an open-label, single-center study.  Fifty evaluable subjects in three different 
arms (30 in arm 1 and 10 in arms 2 and 3) will be enrolled into the study. 
• The primary objective is to compare the difference in signal between metastatic and 
normal nodes in prostate, kidney and bladder cancer patients. 
• For determining the difference in signal between metastatic and normal nodes 
patients will be infused 7.5mg/kg Fe dose of Ferumoxytol. 
• Subjects with documented prostate or bladder or kidney cancer will undergo pre-
infusion and 24, 48 hours post-Ferumoxytol infusion MRI consisting of T1 weighted 
(W), T2W and T2*W MRI at 3 Tesla (T) magnet.  
• The difference in signal between metastatic and normal nodes will be determined by 
measuring the difference in signal between tumor and normal node, and determining 
the maximum difference per each imaging time point. 
• Patients will also undergo ultrasound examination pre-infusion and 24, 48 hours post-
Ferumoxytol infusion time points. The signal changes at post-infusion ultrasound will 
be visually evaluated in an exploratory manner. 
7.2 
Sample Size/Accrual Rate 
Thirty evaluable patients in 3 different arms (arm1=prostate cancer, arm 2=bladder cancer, arm 
3=kidney cancer) will be included in this trial with an accrual rate of 1-2 patients a month. A 
patient will be evaluable if he/she completes pre and 24 hours, 48 hours post ferumoxytol 
infusion MRI scans and may undergo surgical excision of the lymph node dissection or needle 
biopsy of the lymph node or completes the clinical assessment including conventional imaging 
evaluation.  In order to allow for the possibility of a small number of inevaluable patients, the 
accrual ceiling will be set least 56. Therefore, it is expected that this study will be completed 
within 2 years. 
7.3 
Stratification Factors 
• 
Arm 1 


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• Subject must have a documented diagnosis of prostate cancer with evidence of 
lymph node involvement (with a short axis diameter of ≥1.5cm)  
• 
Arm 2 
• Subject must have a documented diagnosis of bladder cancer (transitional cell 
carcinoma) with evidence of lymph node involvement (with a short axis diameter 
of ≥1.5cm) 
• 
Arm 3 
• Subject must have a documented diagnosis of kidney cancer (all types of renal 
cell cancer) with evidence of lymph node involvement (with a short axis diameter 
of ≥1.5cm) 
All patients will receive a dose of 7.5mg/kg Fe Ferumoxytol. 
7.4 
Analysis of Primary Endpoint 
The primary objective of the ferumoxytol study is to compare the difference in pre-post 
ferumoxytol infusion signal change between metastatic and normal nodes in prostate, kidney and 
bladder cancer patients. Based on the previous study (Neoplasia, 2007), the mean signal drop of 
benign lymph nodes was 6.3. In comparison, most of the malignant nodes showed little change in 
signal with mean signal drop equal to 0.63. The standard deviation of signal change was similar 
for benign and malignant nodes and equaled 1.7 approximately. 
Each patient is expected to have at least 1-2 benign lymph nodes and 1-2 metastatic nodes. For 
the purpose of sample size calculation, we use the conservative assumption that each patient has 
only one benign and one metastatic node and there is no correlation between benign lymph and 
metastatic node in pre-post ferumoxytol infusion signal change. With 10 patients for each cancer, 
the study has 93% power to detect a minimal mean signal change of three with the two-sided 
paired t-test at the 5% significance level. The power will increase if each patient has signals 
observed in multiple benign lymph nodes and metastatic nodes, as well as if the signal changes 
in benign and metastatic node are positively correlated.  Thus, a total of 30 patients, 10 for each 
cancer are sufficient to achieve adequate power for the primary objective of the study. In order to 
allow for the possibility of a small number of unevaluable patients, the accrual ceiling will be set 
at 36 patients.  
If each patient has multiple and unequal number of benign lymph nodes and metastatic nodes, 
the linear mixed effects model will be used to model and test the difference of signal changes 
between benign lymph and metastatic nodes, where the random intercept is used to account for 
the within-patient correlation of signal changes of multiple nodes. 
7.5 
Analysis of Secondary Endpoints 
The secondary endpoint of this study is to determine the most optimal timing for imaging: 24 
hours vs. 48 hours post infusion.  
One secondary objective of the study is to determine the most optimal timing for imaging: 24 
hours vs. 48 hours post infusion. All the enrolled patients will be imaged at both time points post 
infusion, and signal change at both time points will be calculated. The time point with larger 
separation between metastatic and normal nodes with respect to post-infusion signal change will 
be considered the optimal timing for imaging. 


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30 
 
Another second objective of the study is to use an ultrasound scan to evaluate visually 
(qualitatively) if there is agent uptake. The ultrasound scan will be done before infusion and 24 
hours, 48 hours after infusions.  This second objective is exploratory, and as such summary 
statistics such as the proportion of agent take at each time point and the corresponding standard 
error will be reported. In order to account for the intra-patient correlation of agent uptake of 
multiple nodes, the linear mixed effects model with the random intercept will be used to estimate 
the proportion of agent uptake at each time point. 
8 
PHARMACEUTICAL INFORMATION 
8.1 
Ferumoxytol 
8.1.1 Source 
Ferumoxytol is a commercial drug. It will be purchased by the NIH Clinical Center Pharmacy, 
and billed to the Molecular Imaging Program. 
8.1.2 Route of Administration:  
 
 
Intravenous 
8.1.3 Method of Administration: 
 
Ferumoxytol will be administered as an intravenous infusion in 50-200 mL 0.9% Sodium 
Chloride Injection, USP or 5% Dextrose Injection, USP over at least 15 minutes.   
 
8.1.4 Formulation and preparation  
Feraheme (30 mg/mL) is available for intravenous injection in single use vials. Each vial 
contains 510 mg of elemental iron in 17 mL. 
8.1.5 Stability and Storage  
Store at controlled room temperature (20
o to 25
oC [68
o to 77
oF]). Excursions permitted to 15
o – 
30
oC (59
o – 86
oF).  
8.1.6 Agent Ordering 
Ferumoxytol is a commercial drug. It will be purchased by the NIH Clinical Center pharmacy, 
and billed to the Cancer Imaging Program. 
8.1.7 Agent Administration 
Ferumoxytol will be administered as an intravenous infusion in 50-200 mL 0.9% Sodium 
Chloride Injection, USP or 5% Dextrose Injection, USP over at least 15 minutes..  
8.1.8 Toxicity 
• Hypersensitivity reactions (anaphylaxis and/or anaphylactoid reactions) 
• Hypotension 
• Iron overload 
• Diarrhea 
• Nausea  
• Dizziness  


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• Constipation 
• Peripheral edema 
9 
HUMAN SUBJECTS PROTECTIONS  
9.1 
Rationale For Subject Selection 
Subject must be ≥18 years old, with a documented diagnosis of prostate, bladder or kidney 
cancer (for arm 1, which includes prostate cancer only patients, subjects will be male). 
Subjects may be scheduled for clinically indicated surgical resection or needle biopsy of the 
lymph node due to strong suspicion of harboring metastatic lymph nodes. 
9.2 
Participation of Children 
Prostate, bladder and kidney cancers are not seen in children.  Thus, we will not include children 
in this study. 
9.3 
Participation of Subjects Unable to Give Consent 
Adults unable to give consent are excluded from enrolling in the protocol.  However re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is minor increase over minimal risk 
from research participation (section 9.4), all subjects ≥ age 18 will be offered the opportunity to 
fill in their wishes for research and care, and assign a substitute decision maker on the “NIH 
Advance Directive for Health Care and Medical Research Participation” form so that another 
person can make decisions about their medical care in the event that they become incapacitated 
or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH 
Ability to Consent Assessment Team for evaluation.  For those subjects that become 
incapacitated and do not have pre-determined substitute decision maker, the procedures 
described in MEC Policy 87-4 for appointing a surrogate decision maker for adult subjects who 
are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of 
attorney, will be followed. 
9.4 
Evaluation of Benefits and Risks/Discomforts 
There is no possibility of direct benefit to participants in this study.  The results of this trial could 
generate generalizable information that may benefit future patients with prostate cancer and 
therefore, subjects may benefit by knowing they have contributed to scientific knowledge.   
The risks for participating are also small.  Because the risks of Ferumoxytol infusion and MR are 
uncommon, we anticipate a low rate of adverse events at any 3 arm in this study.    
Specific risks and potential complications will be clearly outlined in a separate consent form at 
the time of each procedure.  Most complications are expected to be minor and require no 
treatment.  Risks and discomforts associated with Ferumoxytol infusion and imaging are 
discomfort of an IV placement and the theoretical effects allergic reaction.  The subject will be 
required to lay still on their back for back for 5-7 minutes for the MRI scan.  
A licensed clinical practitioner will be immediately available during the infusion and imaging 
period and they will be backed by the Clinical Center’s Code team.  If hospitalization is required 
the participant will be admitted.  However, this is unlikely to occur based on what is known of 
this agent.  There is an added inconvenience of having to return for follow-up scan (at 24 and 48 
hours) that the subjects will be made aware of.   


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Adverse events will be reviewed after every case and a decision will be made about moving 
forward to the next participant so that each participant will have the benefit of the prior 
participant’s experience. 
As this is a new imaging agent, the alternative is to choose not to participate. 
9.5 
Consent and Assent Process and Documentation 
The participant will be informed of the study by a member of the Urological Oncology Branch, 
Radiation Oncology Branch,  or Genitourinary Malignancies Branch research team and the 
subject will be contacted by the study research nurse who will explain the study in detail and 
provide a copy of the consent form and protocol (if requested) to the participant.  If the 
participant has any questions they will be answered by telephone.  A signed consent will be 
obtained by the principal investigator or an associate investigator on the day of the initial MR.  
The original signed consent goes to Medical Records; a copy is placed in the research record. 
 
9.5.1 Telephone consent  
The informed consent document will be sent to the subject.  An explanation of the study will be 
provided over the telephone after the subject has had the opportunity to read the consent form.  
The subject will sign and date the informed consent. A witness to the subject’s signature will 
sign and date the consent. 
The original informed consent document will be sent back to the consenting investigator who 
will sign and date the consent form with the date the consent was obtained via telephone.   
A fully executed copy will be returned via mail for the subject’s records. 
The informed consent process will be documented on a progress note by the consenting 
investigator and a copy of the informed consent document and note will be kept in the subject’s 
research record. 
 
9.5.2 Informed consent of non-English speaking subjects 
If there is an unexpected enrollment of a research participant for whom there is no translated 
extant IRB approved consent document, the principal investigator and/or those authorized to 
obtain informed consent will use the Short Form Oral Consent Process as described in MAS 
Policy M77-2, OSHRP SOP 12, and 45 CFR 46.117 (b) (2). The summary that will be used is the 
English version of the extant IRB approved consent document.  Signed copies of both the 
English version of the consent and the translated short form will be given to the subject or their 
legally authorized representative and the signed original will be filed in the medical record. 
Unless the PI is fluent in the prospective subject’s language, an interpreter will be present to 
facilitate the conversation (using either the long translated form or the short form). Preferably 
someone who is independent of the subject (i.e., not a family member) will assist in presenting 
information and obtaining consent. Whenever possible, interpreters will be provided copies of 
the relevant consent documents well before the consent conversation with the subject (24 to 48 
hours if possible).  


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We request prospective IRB approval of the use of the short form process for non-English 
speaking subjects and will notify the IRB at the time of continuing review of the frequency of the 
use of the Short Form. 


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noninvasive lymph node evaluation. Urology, 2005. 66(5): p. 1066-71. 
43. 
Guimaraes, A.R., et al., Pilot study evaluating use of lymphotrophic nanoparticle-
enhanced magnetic resonance imaging for assessing lymph nodes in renal cell cancer. 
Urology, 2008. 71(4): p. 708-12. 
44. 
Lahaye, M.J., et al., USPIO-enhanced MR imaging for nodal staging in patients with 
primary rectal cancer: predictive criteria. Radiology, 2008. 246(3): p. 804-11. 
45. 
Birkhauser, F.D., et al., Combined ultrasmall superparamagnetic particles of iron oxide-
enhanced and diffusion-weighted magnetic resonance imaging facilitates detection of 
metastases in normal-sized pelvic lymph nodes of patients with bladder and prostate 
cancer. Eur Urol, 2013. 64(6): p. 953-60. 


Abbreviated Title: Ferumoxytol MRI in GU Cancers 
Version Date: 12-20-2016 
37 
 
46. 
Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47. 
 
. 


Abbreviated Title: Ferumoxytol MRI in GU Cancers 
Version Date: 12-20-2016 
38 
 
11 APPENDICES 
11.1 APPENDIX A: EXCERPT FROM FERUMOXYTOL PACKAGE INSERT [4] 
Ferumoxytol 
(NSC 729745) 
Other Names:  
Code 7228 
CAS Registry Number: 
 
1309-38-2 
Molecular Formula:  
FeO1.49 (approximately);C398H646O337 (coating) 
 
Description: 
 
Ferumoxytol is a non-stoichiometric magnetite (superparamagnetic iron oxide) coated with 
polyglucose sorbitol carboxymethylether. The overall colloidal particle size is 17-31 nm in diameter. 
The chemical formula of Ferumoxytol is Fe5874O8752-C11719H18682O9933Na414 with an apparent molecular 
weight of 750 kDa. 
How Supplied: 
 
Ferumoxytol is supplied as a sterile, single-use, vial.  Each 510 mg vial contains 17 mL of a black to 
reddish brown liquid of 30 mg Fe/mL and 44 mg/mL of mannitol.  The formulation is isotonic with 
an osmolality of 270-330 mOsm/kg. The product contains no preservatives, and has a pH of 6 to 8. 
Preparation:   
No additional preparation is necessary unless otherwise directed in the protocol. 
Storage: 
 
The intact vials should be stored at controlled room temperature 20-25oC (68-77oF).  Excursions 
permitted to 15o-30oC (59o-86oF) 
Stability: 
 
The intact vials remain clinically acceptable until the expiration date indicated on the vial. 
CAUTION:  The single-use dosage form contains no antibacterial preservatives.  
Therefore, it is advised that the product be discarded 6 hours after initial entry.  
Route of Administration:  
 
 
Intravenous 
Method of Administration: 
 
Ferumoxytol will be administered as an intravenous infusion in 50-200mL 0.9% Sodium Chloride, 
USP or 5% Dextrose Injection, USP over at least 15 minutes.   
 


Abbreviated Title: Ferumoxytol MRI in GU Cancers 
Version Date: 12-20-2016 
39 
 
ADVERSE REACTIONS: Feraheme injection may cause serious hypersensitivity reactions and 
hypotension.  
In clinical studies, 1,726 subjects were exposed to Feraheme; 1,562 of these had CKD and 164 
did not have CKD. Of these subjects 46% were male and the median age was 63 years (range of 
18 to 96 years).  
Because clinical trials are conducted under widely varying conditions, adverse reaction rates 
observed in the clinical trials of a drug may not reflect the rates observed in practice.  
ADVERSE REACTIONS IN CLINICAL STUDIES:  
Across the three randomized clinical trials, a total of 605 patients were exposed to two injections 
of 510 mg of Feraheme and a total of 280 patients were exposed to 200 mg/day of oral iron for 
21 days. Most patients received their second Feraheme injection 3 to 8 days after the first 
injection.  
Adverse reactions related to Feraheme and reported by ≥ 1% of Feraheme-treated patients in the 
randomized clinical trials are listed in Table 1. Diarrhea (4.0%), constipation (2.1%) and 
hypertension (1.0%) have also been reported in Feraheme-treated patients.  
Table 1: Adverse Reactions to Feraheme 
Reported in ≥1% of Patients with CKD Adverse 
Reactions  
Feraheme 2 x 510 
mg (n = 605)  
Oral Iron (n = 
280)  
Nausea  
3.1%  
7.5%  
Dizziness  
2.6%  
1.8%  
Hypotension  
2.5%  
0.4%  
Peripheral Edema  
2.0%  
3.2%  
Headache  
1.8%  
2.1%  
Edema  
1.5%  
1.4%  
Vomiting  
1.5%  
5.0%  
Abdominal Pain  
1.3%  
1.4%  
Chest Pain  
1.3%  
0.7%  
Cough  
1.3%  
1.4%  
Pruritus  
1.2%  
0.4%  
Pyrexia  
1.0%  
0.7%  
Back Pain  
1.0%  
0%  
Muscle Spasms  
1.0%  
1.4%  
Dyspnea  
1.0%  
1.1%  
Rash  
1.0%  
0.4%  


Abbreviated Title: Ferumoxytol MRI in GU Cancers 
Version Date: 12-20-2016 
40 
 
11.2 APPENDIX B: Performance Status Criteria 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-
disease performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically 
strenuous activity, but ambulatory and able to carry out 
work of a light or sedentary nature (e.g., light housework, 
office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all 
self-care, but unable to carry out any work activities.  Up 
and about more than 50% of waking hours. 
3 
In bed >50% of the time.  Capable of only limited self-
care, confined to bed or chair more than 50% of waking 
hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on 
any self-care.  Totally confined to bed or chair. 
5 
Dead. 
 
 
 

ICF_001.pdf: 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
INSTITUTE: 
National Cancer Institute 
STUDY NUMBER: 
14-C-0107 
PRINCIPAL INVESTIGATOR: 
Baris Turkbey, MD
STUDY TITLE:  
Evaluation of Ferumoxytol Enhanced MRI for the Detection of Lymph Node Metastases 
in Genitourinary (Prostate, Bladder And Kidney) Cancers 
Continuing Review Approved by the IRB on 01/08/18 
Amendment Approved by the IRB on 01/18/17 (D) 
 
Date posted to web: 01/24/18 
Standard 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
INTRODUCTION 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
Taking part in NIH research is entirely voluntary.  
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation. 
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future. 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study. 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional.   
Purpose of the Study 
The purpose of this study is to help researchers determine how well Ferumoxytol can detect 
lymph node metastases in patients with prostate, bladder, or kidney cancer. Ferumoxytol is an 
FDA-approved iron replacement therapy agent.  However, it is NOT approved by the FDA as an 
imaging agent. So the use Ferumoxytol in this protocol is experimental. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  14-C-0107 
CONTINUATION: page 2 of 9 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Why are you being asked to take part in this study? 
You are being invited to take part in a research study because you have one of the following 
types of cancers: prostate, bladder, or kidney and you may have surgery to remove your cancer 
or a biopsy to remove some tissue from your lymph nodes here at the Clinical Center.  The 
decision to have surgery or a biopsy will not be made as a part of this study.   
This study will not affect your ability to take part in other research protocols or receive medical 
care. 
How many people will take part in this study?  
Up to 56 people will be included in this study. 
What will happen if you take part in this research study?   
Before you begin the study 
For your safety, and to help make sure the results of this trial are scientifically meaningful, your 
medical history will be reviewed to make sure you are eligible to take part.   
At your first study visit, three vials of blood will be drawn for a panel of routine blood tests, you 
will have a physical exam, and your vital signs (blood pressure, heart rate, breathing rate and 
temperature) will be measured.  If you are a woman able to get pregnant, you will also have a 
pregnancy test done. You will also answer questions about your medical history and current 
medications.   
During the study 
If you are eligible for this study and wish to participate, you will then be scheduled for study 
procedures including ultrasonography, MRI imaging and Ferumoxytol infusion.  These activities 
will be performed in the NCI Molecular Imaging Clinic except for the ultrasonography, which 
will be performed in the Radiology and Imaging Sciences Department of Clinical Center, NIH.   
If you are women, an additional pregnancy test will also be done within 48 hours prior to 
Ferumoxytol infusion if more than 48 hours have passed since the screening test. 
The first MRI before Ferumoxytol infusion will take approximately 1 hour, whereas the first 
ultrasound examination will take about 10-15 minutes.  Twenty-four hours after Ferumoxytol 
infusion, you will have a second MRI scan and an ultrasound examination, which will again take 
approximately 1 hour and 10-15 minutes, respectively. Finally, forty-eight hours after 
Ferumoxytol infusion, you will have a third MRI scan and an ultrasound examination. 
Ultrasonography is a medical imaging technique used to visualize internal organs to capture their 
size, structure and any pathological lesions with real time images. This technique uses harmless 
sound waves to provide pictures of organs or tissues inside the body.  
During the MRI scan, a standard sensor, which is like a small blanket with wiring inside, will be 
wrapped around your lower torso to improve MRI quality.  The MRI scan usually takes less than 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  14-C-0107 
CONTINUATION: page 3 of 9 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
an hour.  You will need to lie still on the scanning table during that time.  An intravenous line 
(IV; a very thin catheter inserted into a vein with a tiny needle) will be started after your first 
MRI scan and Ferumoxytol will be injected into your system as an  IV infusion.  You will 
receive more information about your MRI scan when you visit the Molecular Imaging Clinic and 
you may ask questions at any time.  In addition, you should ask your doctor or the study doctor 
any questions you have concerning this study. 
After imaging has been completed, your referring physician will treat your disease per the 
treatment protocol you are enrolled on. 
If you have surgery to remove lymph nodes or a biopsy after the MRI scan, your tissue will be 
reviewed in the NCI pathology department to determine if the imaging agent was able to detect 
involvement of your lymph nodes.  
If you do not have surgery to remove lymph nodes or a biopsy, the research team will review 
your medical records to determine if the imaging agent was able to detect involvement of your 
lymph nodes.  
Birth Control 
If you are a woman who is breast feeding, pregnant, or planning to become pregnant during the 
study, you may not take part in the study because we don’t know how this medicine would affect 
your baby or your unborn child. If you are a woman who can become pregnant, or are the partner 
of a woman who can become pregnant, you will need to practice an effective form of birth 
control before starting study treatment, during study treatment, and for 1 day after you finish 
study related imaging. If you think that you or your partner is pregnant, you should tell your 
study doctor or nurse at once.   
Effective forms of birth control include:  
• abstinence  
• intrauterine device (IUD) 
• tubal ligation 
• vasectomy 
Some methods of birth control will not work when you are taking certain drugs. You can still 
become pregnant even if you use an acceptable birth control method. 
Women who become pregnant during the study will have to leave the study.  The study doctor 
may ask for information about the pregnancy and the birth of the baby.  The study doctor may 
share this information with the sponsor and the institutional review board/research ethics board 
that reviews this study. 
If you are a woman of childbearing potential: 
By signing this consent form, you confirm to the best of your knowledge that you are not 
pregnant now and you do not intend to become pregnant during this study.  


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  14-C-0107 
CONTINUATION: page 4 of 9 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
A serum (blood draw) or urine pregnancy test will be done to confirm that you are not pregnant 
48 hours prior to any imaging session. If you are found to be pregnant, you will not be given the 
infusion or undergo imaging and you will be removed from the study. 
If at any later time during this study you think you might be pregnant, or later learn that you were 
pregnant during the study, you must contact the study doctor immediately for further instructions 
about your participation in this study and what to do next 
How long will you be in the study? 
Participation in this study will last until you have had the forty-eight hour ultrasonography and 
MRI completed. The active part of the study, (Ferumoxytol infusion, ultrasonography, and MRI 
scanning) will last a few days.   
However, patients that do not undergo surgical excision or a biopsy to remove lymph nodes will 
remain on study for a minimum of 12 months. 
It is expected to take approximately 24 months for this study to enroll all patients. 
What do I have to do? 
Read this informed consent and take the time to get answers to all your questions. You will be 
provided a copy of this consent once you, the investigator and a witness have signed the form.  
You will need to provide your doctor with a listing of all your current medications as certain 
medications may react with the study infusion.  
What are the possible risks / discomforts? 
Risk from Blood Draws 
The risks associated with the blood draws and IV insertion includes: 
• pain at the needle site; 
• bruising; 
• possible dizziness if you stand up quickly; and  
• possible inflammation of the vein or infection at the needle site. 
Risks from Ultrasonography 
The ultrasonography procedure will take about 10-15 minutes. Ultrasonography has no known 
risks with no use of ionizing radiation or adverse heating or pressure effects in tissue. 
Risks from MRI 
Having an MRI requires that you lie still with part of you or all of you inside a tube shaped 
machine for about 45 minutes to an hour.  Even with the ear plugs we give you it can be noisy 
with loud clicking and thumping sounds, which bothers some people.  Some people may feel 
’closed in’ or ‘trapped’ (even though they being closely watched and are quite safe).  This is 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  14-C-0107 
CONTINUATION: page 5 of 9 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
called claustrophobia. Cool air will surround you, and the room is large and brightly lit to help 
avoid claustrophobia.  You may ask your physician for a mild sedative for the procedure if you 
think it will help.  If you take a sedative you must not drive a vehicle until it wears off after the 
MRI. 
MRI scans cannot be done on people who have: 
• 
a cardiac pacemaker,  
• 
neural pacemaker,  
• 
surgical metal clips in the brain or on blood vessels,  
• 
cochlear implants,  
• 
or foreign metal objects within the eye.   
At the time of your MRI, you will be asked about these things. 
Risks from Ferumoxytol 
Ferumoxytol has been generally safe when given to people for its FDA approved purpose of iron 
replacement therapy.  Side effects, some of which can be serious or life threatening, may 
sometimes occur.  These side effects, though rare, may happen in this trial.  If they do happen it 
is usually right around the time that Ferumoxytol is injected, which is why you will be closely 
watched at that time, and promptly treated if necessary.  These effects include:  
• whole body allergic reactions, which can range from mild to serious or life threatening 
(this is called anaphylaxis),  
• low blood pressure, which can lead to becoming unconscious (fainting, passing-out) 
• iron overload.  
One person who took part in a prior study in NCI experienced a mild allergic reaction while the 
Ferumoxytol was being given.  It was promptly treated and got better right away.  Again, you 
will be closely observed during and right after the Ferumoxytol is given so that if any reaction 
occurs it can be immediately treated.   The dose used in this study is less than that used for iron 
replacement therapy.  It is always possible that you may experience some side effects that we 
cannot anticipate. 
What are the possible benefits of taking part? 
There is no anticipated direct benefit to participating in this study, but you may help others that 
have cancer by contributing to cancer research. 
What are the alternatives for diagnosis or treatment? 
This is not a treatment trial. The alternative is not to participate.  If you do not consent to this 
trial, you will not be deprived of any treatment for which you are otherwise entitled.  
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  14-C-0107 
CONTINUATION: page 6 of 9 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Stopping Participation in this study 
Your study doctor may remove you from the study if:  
• they think it is in your best interest;  
• if you do not follow the study instructions; or  
• if you are found to be pregnant before you receive Ferumoxytol 
• for administrative reasons 
In this case, you will be informed of the reason your participation is being stopped. 
You can stop taking part in the study at any time. However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first. 
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, any data generated from the scans that 
have already been distributed to other researchers or placed in the research databases cannot be 
recalled and destroyed. 
What if relevant new information becomes available? 
If new information that might affect your decision to be in the study becomes available, your 
physician will tell you about it and discuss whether you want to continue on the study.  If you 
decide not to carry on, this will not influence your care.  If you decide to continue in the study 
you will be asked to sign an updated consent form. 
Research Subject’s Rights 
What are the costs of taking part in this study?  
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
• You will receive study treatment at no charge to you. This may include surgery, 
medicines, laboratory testing, x-rays or scans done at the Clinical Center, National 
Institutes of Health (NIH), or arranged for you by the research team to be done 
outside the Clinical Center, NIH if the study related treatment is not available at the 
NIH.  
• There are limited funds available to cover the cost of some tests and procedures 
performed outside the Clinical Center, NIH.  You may have to pay for these costs if 
they are not covered by your insurance company. 
• Medicines that are not part of the study treatment will not be provided or paid for by 
the Clinical Center, NIH. 
• Once you have completed taking part in the study, medical care will no longer be 
provided by the Clinical Center, NIH. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  14-C-0107 
CONTINUATION: page 7 of 9 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results.  You can search this Web site at any time. 
Will your medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Organizations that may look at 
and/or copy your medical records for research, quality assurance, and data analysis include: 
• The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people. 
• National Cancer Institute Institutional Review Board 
Conflict of Interest 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide. You may ask your research 
team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to 
report their personal finances to the NIH. 
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest. 
 
 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:  14-C-0107 
CONTINUATION: page 8 of 9 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
OTHER PERTINENT INFORMATION 
1. 
Confidentiality.  When results of an NIH research study are reported in medical journals 
or at scientific meetings, the people who take part are not named and identified.  In most cases, 
the NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
2. 
Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-
term medical care for any injury resulting from your participation in research here.  In general, 
no long-term medical care or financial compensation for research-related injuries will be 
provided by the National Institutes of Health, the Clinical Center, or the Federal Government.  
However, you have the right to pursue legal remedy if you believe that your injury justifies such 
action. 
3. 
Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines. 
4. 
Problems or Questions.  If you have any problems or questions about this study, or 
about your rights as a research participant, or about any research-related injury, contact the 
Principal Investigator, Dr. Baris Turkbey; Bldg 10, Room B3B69, 10 Center Drive, Bethesda, 
MD 20892; Telephone: 240-760-6112.  You may also call the Clinical Center Patient 
Representative at 301-496-2626. 
5. 
Consent Document.  Please keep a copy of this document in case you want to read it 
again. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:  14-C-0107 
CONTINUATION: page 9 of 9 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby consent to 
take part in this study. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby give 
permission for my child to take part in this 
study.   
(Attach NIH 2514-2, Minor’s Assent, if 
applicable.) 
 
  
  
 
 
 
Signature of Adult Patient/ 
Legal Representative 
Date 
Signature of Parent(s)/ Guardian Date 
 
 
Print Name 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to 
participate in the study. 
 
  
  
 
Signature of Parent(s)/Guardian 
Date 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM JANUARY 08, 2018 THROUGH JANUARY 07, 2019.  
 
 
 
 
 
 
 
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
 
Print Name 
 
 
Print Name