Clinical trial NCT01867424
Conditions: Prostate Cancer
Keywords: Testosterone Membrane Transporter OATP1B3 Castration Resistant Prostate Cancer Prostatectomy Gadolinium-Based Contrast Agent
Sponsor: National Cancer Institute (NCI)
Start date: 2013-05-14; Completion date: 2016-12-08
Enrollment: 24 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Background:

\- Prostate cancer is the most common cancer type among men. Some prostate cancers respond to hormonal therapy. However, some cell characteristics of other prostate cancers cause it not to respond as well to these therapies. Researchers want to see if gadoxetate, a contrast agent used to help identify damaged liver tissue, can help tell these types of prostate cancer apart. It may be able to identify if a man has a type of prostate cancer for which hormone therapy may not work as well.

Objectives:

\- To see if gadoxetate can help identify different types of prostate cancers during imaging studies.

Eligibility:

\- Men at least 18 years of age who have prostate cancer. Participants will be having surgery to either remove the prostate or take tumor tissue samples.

Design:

* Participants will be screened with a physical exam and medical history. Blood samples will be collected.
* Participants will have a magnetic resonance imaging (MRI) scan of the lower torso. They will receive gadoxetate during the MRI scan.
* Participants who have surgery will have a sample of their tumor cells collected. Those who have a biopsy will provide cells from this biopsy for study.
* Treatment will not be provided as part of this study.

Detailed description:
BACKGROUND:

* Prostate cancer is the most common non-cutaneous malignancy among men in the western world. Prognostic biomarkers would be useful in stratifying patients to different treatments.
* The expression of a testosterone membrane transporter, organic anion-transporting polypeptide 1B3 (OATP1B3), is associated with shorter time to progression after hormonal ablation therapy and shorter overall survival in prostate cancer patients. 52% of localized prostate cancer lesions express OATP1B3, while 92% of prostate cancer metastases requiring hormonal ablation treatment, express OATP1B3 in soft tissue lesions. Expression of OATP1B3 also correlates with Gleason grade.
* Current imaging methods cannot predict treatment failure or resistance.
* Gadoxetate disodium (Gd-EOB-DTPA) (Eovist , Bayer HealthCare Pharmaceuticals Inc. Pittsburgh, PA) is an MR imaging agent which is FDA-approved gadolinium chelate for detecting hepatocellular carcinoma (HCC), as normal hepatocytes express OATP1B3 while most hepatocellular carcinomas (HCC) do not. However, those HCCs that do take up Eovist have been shown to express OATP1B3.
* Eovist may be useful to evaluate OATP1B3 status in patients with prostate cancer and may therefore serve as a prognostic and treatment biomarker.

PRIMARY OBJECTIVE:

-Evaluate the uptake and retention of Eovist in prostate cancers.

ELIGIBILTY:

* Male subjects greater than or equal to 18 years old
* Eastern Cooperative Oncology Group (ECOG) Performance score of 0 to 2
* Subjects with clinically localized prostate cancer must have image guided biopsy confirmed prostate cancer and sufficient tissue available for OATP1B3 immunohistochemistry (IHC).
* Subjects with advanced disease who have failed hormone therapy and who have sufficient tissue from a soft tissue or metastatic bone lesion (measuring greater than or equal to1.5cm in diameter at computed tomography (CT) or magnetic resonance imaging (MRI) scan) available for OATP1B3 IHC.

or

-Subjects, for whom tissue is not available, must have a soft tissue or metastatic bone lesion that can be biopsied and be willing to undergo percutaneous biopsy to obtain tissue for OATP1B3 expression.

DESIGN:

* This pilot study will accrue 25 subjects divided into two arms: 10 evaluable subjects with localized prostate cancer and 15 evaluable subjects with advanced disease
* Each subject will receive a single intravenous (IV) dose of Eovist by bolus injection
* All subjects will undergo magnetic resonance imaging (MRI) prior to and immediately after, 10, 20 and 60 minutes post-Eovist injection

Arms: arm 1: Advanced disease: who have failed hormone therapy and who have sufficient tissue from a soft tissue or metastatic bone lesion (measuring 1.5cm in diameter at computed tomography (CT) or magnetic resonance imaging (MRI) scan) available for organic anion-transporting polypeptide 1B3 (OATP1B3) immunohistochemistry (IHC) or must have a soft tissue or metastatic bone lesion that can be biopsied and be willing to undergo percutaneous biopsy to obtain tissue for OATP1B3 expression. arm 2: Localized disease: must have image guided biopsy confirmed prostate cancer and sufficient tissue available for OATP1B3 IHC.
Interventions: intervention 1: Eovist
Intervention descriptions: intervention 1: 0.1 ml/kg Eovist will be administered intravenous (IV) to each patient

Protocol documents:
Prot_SAP_ICF_000.pdf: 
Amendment
Protocol Number:
13C0145-D
Principal Investigator: Baris Turkbey 
NCI 
MIP 
301.443.2315 
turkbeyi@mail.nih.gov
(NIH Employee Name, Institute/Branch, Telephone and e-mail)
Reference Number:
347185
Protocol Title:
Pilot Study of Eovist® (Gadoxetate) Enhanced MRI for the Detection of Prostate Cancer
SIGNATURES
Principal Investigator (*): 
Baris Turkbey - applied signature on 05/06/2015 10:32 AM EDT
Accountable Investigator:
Peter Choyke - applied signature on 05/06/2015 1:24 PM EDT
Branch Chief/CC Department Head (**):
Peter Choyke - applied signature on 05/06/2015 1:22 PM EDT
Medical Advisory Investigator (if applicable):
N/A
Lead Associate Investigator signature:
N/A
Referral Contact signatures:
N/A
Associate Investigators signatures:
N/A
For Institute/Center Scientific Review Committee:
N/A
Other IC Clinical Director signatures:
N/A
APPROVALS
IRB Chair:
Michael Hamilton - applied signature on 05/12/2015 9:20 AM EDT
Clinical Director:
James L Gulley, MD PhD - applied signature on 05/12/2015 9:38 AM EDT
CONCURRENCE
OPS Protocol Specialist:
Signature                                                         Print Name                                              Date
* Signature signifies that investigators on this protocol have been informed that the collection and use of personally identifiable information at 
the NIH are maintained in a system of record governed under provisions of the Privacy Act of 1974. The information provided is mandatory for 
employees of the NIH to perform their assigned duties as related to the administration and reporting of intramural research protocols and 
used solely for those purposes.  Questions may be addressed to the Protrak System Owner. 
** I have reviewed this research project and considered the NIH Policy for Inclusion of Women and Minorities in Clinical Research. Taking into 
account the overall impact that the project could have on the research field involved, I feel the current plans adequately includes both sex/
gender, minorities, children, and special populations, as appropriate. The current enrollment is in line with the planned enrollment report for 
inclusion of individuals on the basis of their sex/gender, race, and ethnicity and is appropriate and of scientific and technical merit. 
IRB Meeting Date:
Expedited
DEC Clearance Date:
NA
Protocol Version Date:05/04/2015
Tiffany Johnson
AM D
5/12/2015


Abbreviated Title: Eovist® MRI of prostate cancer 
Version Date: 05/04/2015 
 
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Protocol Number: 13-C-0145D 
Protocol Title: Pilot study of Eovist® (gadoxetate) enhanced MRI for the detection of 
prostate cancer 
Principal Investigator:  
Ismail Baris Turkbey M.D. 
Molecular Imaging Program, CCR, NCI 
Building 10, Room B3B85 
Bethesda, MD 20892 
Tel: 301-443-2315 
turkbeyi@mail.nih.gov  
Lead Associate Investigator:  
William Douglas Figg, Pharm.D. 
Genitourinary Malignancies Branch (GMB), CCR, NCI 
Building 10, Room 5A01 
Bethesda, MD 20892 
Tel: 301-402-3623 
wdfigg@helix.nih.gov  
Associate Investigators: 
Peter L. Choyke, M.D. 
MIP, CCR, NCI 
Building 10, Room B3B69 
Bethesda, MD 20892 
Tel: 301-402-8409 
pchoyke@nih.gov  
Karen Kurdziel, M.D. 
MIP, CCR, NCI 
Building 10, Room B3B69F 
Bethesda, MD 20892 
Tel 301-443-0622 
kurdielk@mail.nih.gov  
William Dahut, M.D. 
GMB, CCR, NCI 
Building 10, Room 13N240E 
Bethesda, MD 20892 
Tel: 301-435-8183 
dahutw@mail.nih.gov  
Andrea Apolo, M.D. 
GMB, CCR, NCI 
Building 10, Room 12N226 
Bethesda, MD 20892 
Tel: 301-496-4916 
Andrea.apolo@nih.gov 
Aradhana Kaushal, M.D. 
Radiation Oncology Branch, CCR, NCI 
Building 10, Room B2-3681 
Bethesda, MD 20892 
Tel: 301-496-5457 
kaushala@mail.nih.gov  


Abbreviated Title: Eovist® MRI of prostate cancer 
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Peter A. Pinto, M.D. 
Urologic Oncology Branch, CCR, NCI 
Building 10, Room 2-5952 
Bethesda, MD 20892 
Tel: 301-496-6353 
pintop@mail.nih.gov  
Cindy H. Chau, Pharm.D., Ph.D 
GMB, CCR, NCI 
Building 10, Room 5A01 
Bethesda, MD 20892 
Tel: 301-402-3622 
chauc@mail.nih.gov  
Maria Merino-Neumann, M.D. 
Laboratory of Pathology, CCR, NCI 
Building 10, Room 2B44 
Bethesda, MD 20892 
Tel: 301-402-3623 
mjmerino@mail.nih.gov  
 
Armando Filie, M.D. 
Laboratory of Pathology, CCR, NCI 
Building 10, Room 2A19 
Bethesda, MD 20892 
Tel: 301-496-6355 
afilie@mail.nih.gov  
 
Bradford Wood, M.D. 
Radiology & Imaging Sciences, CC 
Center for Interventional Oncology, NCI 
MSC 1182, Building 10, Room 1C-341 
Bethesda, MD 20892 
Tel: 301-443-8191 
BWood@cc.nih.gov  
 
Yolanda L. McKinney, R.N. 
Office of the Clinical Director (OCD), CCR, NCI 
Building 10, Room B3B69 
Bethesda, MD 20892 
Tel: 301-443-6913 
ymckinney@mail.nih.gov  
Statistician: 
Joanna H. Shih, Ph.D. 
Biometric Research Branch 
Division of Cancer Treatment and Diagnosis 
National Cancer Institute  
 
9609 Medical Center Drive 
 
Room 5-W124 MSC 9735 
Bethesda, MD 20892-9735 
Tel: 240-276-6035 


Abbreviated Title: Eovist® MRI of prostate cancer 
Version Date: 05/04/2015 
 
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Fax: 240-276-7888 
jshih@mail.nih.gov  
Referral Contact:  
Yolanda L. McKinney, R.N. 
OCD, CCR, NCI 
Building 10, Room B3B69 
Bethesda, MD 20892 
Tel: 301-443-6913 
ymckinney@mail.nih.gov  
Drug: Eovist® (Gadoxetate Disodium) 
Manufacturer: Bayer Healthcare Pharmaceuticals Inc 
 


Abbreviated Title: Eovist® MRI of prostate cancer 
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PRECIS 
Background: 
 Prostate cancer is the most common non-cutaneous malignancy among men in the 
western world. Prognostic biomarkers would be useful in stratifying patients to 
different treatments. 
 The expression of a testosterone membrane transporter, OATP1B3, is associated with 
shorter time to progression after hormonal ablation therapy and shorter overall 
survival in prostate cancer patients.  52% of localized prostate cancer lesions express 
OATP1B3, while 92% of prostate cancer metastases requiring hormonal ablation 
treatment, express OATP1B3 in soft tissue lesions.  Expression of OATP1B3 also 
correlates with Gleason grade.  
 Current imaging methods cannot predict treatment failure or resistance.  
 Gadoxetate disodium (Gd-EOB-DTPA) (Eovist®, Bayer HealthCare Pharmaceuticals 
Inc. Pittsburgh, PA) is an MR imaging agent which is FDA-approved gadolinium 
chelate for detecting hepatocellular carcinoma (HCC), as normal hepatocytes express 
OATP1B3 while most hepatocellular carcinomas do not.  However, those HCC’s that 
do take up Eovist® have been shown to express OATP1B3. 
 Eovist® may be useful to evaluate OATP1B3 status in patients with prostate cancer 
and may therefore serve as a prognostic and treatment biomarker.  
Primary Objective: 
 Evaluate the uptake and retention of Eovist® in prostate cancers. 
Eligibility: 
 Male subjects 18 years old 
 ECOG Performance score of 0 to 2 
 Subjects with clinically localized prostate cancer must have image guided biopsy 
confirmed prostate cancer and sufficient tissue available for OATP1B3 IHC. 
 Subjects with advanced disease who have failed hormone therapy and who have 
sufficient tissue from a soft tissue or metastatic bone lesion (measuring ≥1.5cm in 
diameter at CT or MRI scan) available for OATP1B3 IHC. 
 
or 
 Subjects, for whom tissue is not available, must have a soft tissue or metastatic bone 
lesion that can be biopsied and be willing to undergo percutaneous biopsy to obtain 
tissue for OATP1B3 expression. 
Design: 
 This pilot study will accrue 25 subjects divided into two arms: 10 evaluable subjects 
with localized prostate cancer and 15 evaluable subjects with advanced disease  
 Each subject will receive a single IV dose of Eovist® by bolus injection 
 All subjects will undergo MRI prior to and immediately after, 10, 20 and 60 minutes 
post-Eovist® injection 


Abbreviated Title: Eovist® MRI of prostate cancer 
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TABLE OF CONTENTS 
PRECIS ...................................................................................................................................... iv 
Table of Contents........................................................................................................................ 5 
1 
INTRODUCTION .............................................................................................................. 8 
1.1 
Study Objectives .......................................................................................................... 8 
1.1.1 
Primary Objective ................................................................................................. 8 
1.1.2 
Secondary Objective ............................................................................................. 8 
1.1.3 
Exploratory Objective ........................................................................................... 8 
1.2 
Background and Rationale ........................................................................................... 8 
1.2.1 
Study Disease : Prostate Cancer ........................................................................... 8 
1.2.2 
Castration Resistant Prostate Cancer (CRPC) ...................................................... 8 
1.2.3 
OATP1B3 Transports Testosterone and affects clinical outcomes in CaP .......... 8 
1.2.4 
Rationale ............................................................................................................... 9 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT .................................................. 10 
2.1 
Eligibility Criteria ...................................................................................................... 10 
2.1.1 
Inclusion Criteria ................................................................................................ 10 
2.1.2 
Exclusion Criteria ............................................................................................... 10 
2.2 
Screening Evaluation ................................................................................................. 11 
2.2.1 
Screening tests: ................................................................................................... 11 
2.3 
Registration Procedures ............................................................................................. 11 
3 
STUDY IMPLEMENTATION ........................................................................................ 12 
3.1 
Study Design .............................................................................................................. 12 
3.1.1 
Eovist® enhanced MRI ...................................................................................... 12 
3.1.2 
OATP1B3 Genotyping ....................................................................................... 12 
3.1.3 
Pathology ............................................................................................................ 13 
3.1.4 
Immunohistochemistry ....................................................................................... 13 
3.2 
Study Schema............................................................................................................. 14 
3.3 
Study Drug Administration/Administration of Eovist® ............................................ 15 
3.4 
Dose Modifications .................................................................................................... 15 
3.5 
Correlative Studies ..................................................................................................... 15 
3.5.1 
Imaging Correlation ............................................................................................ 15 
3.5.2 
Pathologic and Imaging Correlation ................................................................... 15 
3.5.3 
Histological Correlations .................................................................................... 15 
3.5.4 
Safety Assessments............................................................................................. 15 


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3.6 
Study Calendar ........................................................................................................... 16 
3.6.1 
Study Periods ...................................................................................................... 17 
3.7 
Surgical Guidelines .................................................................................................... 20 
3.8 
Radiation Therapy Guidelines ................................................................................... 20 
3.9 
Off-Study Criteria ...................................................................................................... 20 
3.9.1 
Criteria for Removal from Protocol.................................................................... 20 
4 
CONCOMITANT MEDICATION/MEASURES ............................................................ 21 
5 
DATA COLLECTION AND EVALUATION ................................................................ 21 
5.1 
Data Collection .......................................................................................................... 21 
5.1.1 
Clinical Data ....................................................................................................... 21 
5.1.2 
Safety Data ......................................................................................................... 22 
5.1.3 
Imaging Data ...................................................................................................... 22 
5.2 
Toxicity Criteria ......................................................................................................... 22 
6 
Biospecimen Collection .................................................................................................... 23 
6.1 
Tissue Samples........................................................................................................... 23 
6.2 
Blood Samples ........................................................................................................... 23 
6.3 
Pathology Specimens ................................................................................................. 23 
6.3.1 
Surgical Pathology .............................................................................................. 23 
6.4 
Sample Storage, Tracking and Disposition ................................................................ 23 
6.4.1 
Sample Processing and Storage: ......................................................................... 23 
6.4.2 
Timeframe for research studies .......................................................................... 24 
7 
STATISTICAL Considerations ........................................................................................ 25 
7.1 
Study Populations ...................................................................................................... 25 
7.2 
Subject Characteristics ............................................................................................... 25 
7.3 
Efficacy Analysis ....................................................................................................... 25 
7.3.1 
Primary Efficacy Analysis .................................................................................. 25 
7.3.2 
Secondary Efficacy Analysis .............................................................................. 25 
7.4 
Sample Size Determination........................................................................................ 26 
8 
HUMAN SUBJECTS PROTECTION ............................................................................. 26 
8.1 
Rationale for Subject Selection .................................................................................. 26 
8.2 
Participation of Children ............................................................................................ 26 
8.3 
Evaluation of Benefits and Risks/Discomforts .......................................................... 26 
8.4 
Risks/Benefits Analysis ............................................................................................. 27 
8.5 
Consent and Assent Process and Documentation ...................................................... 27 


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9 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN ........................................................................................................................................ 27 
9.1 
Definitions.................................................................................................................. 27 
9.1.1 
Adverse Events ................................................................................................... 27 
9.1.2 
Suspected adverse reaction ................................................................................. 28 
9.1.3 
Unexpected adverse reaction .............................................................................. 28 
9.1.4 
Serious ................................................................................................................ 28 
9.1.5 
Serious Adverse Event........................................................................................ 28 
9.1.6 
Disability ............................................................................................................ 29 
9.1.7 
Life-threatening adverse drug experience .......................................................... 29 
9.1.8 
Protocol Deviation (NIH Definition) .................................................................. 29 
9.1.9 
Non-compliance (NIH Definition) ..................................................................... 29 
9.1.10 Unanticipated Problem ....................................................................................... 29 
9.2 
NCI-IRB Reporting .................................................................................................... 29 
9.2.1 
NCI-IRB Expedited Reporting of Unanticipated Problems and Deaths ............ 29 
9.2.2 
NCI-IRB Requirements for PI Reporting of Adverse Events at Continuing 
Review 30 
9.3 
Data and Safety Monitoring Plan ............................................................................... 30 
9.3.1 
Principal Investigator/Research Team ................................................................ 30 
10 PHARMACEUTICAL INFORMATION ........................................................................ 31 
10.1 
Eovist® Source....................................................................................................... 31 
10.2 
Toxicity .................................................................................................................. 31 
10.2.1 Pharmacology and Toxicology in Animals ........................................................ 31 
10.2.2 Toxicity in Humans ............................................................................................ 31 
10.2.3 Formulation and Preparation .............................................................................. 31 
10.2.4 Stability and Storage ........................................................................................... 32 
10.2.5 Administration Procedures ................................................................................. 32 
10.2.6 Incompatibilities ................................................................................................. 32 
11 REFERENCES ................................................................................................................. 33 
 


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1 
INTRODUCTION 
1.1 
Study Objectives 
1.1.1 Primary Objective 
 Evaluate the uptake and retention of Eovist® in prostate cancers  
1.1.2 Secondary Objective 
 Evaluate MR contrast enhancement parameters following Eovist® injection with 
respect to Gleason Score and serum PSA levels. 
1.1.3 Exploratory Objective 
 Evaluate MR contrast enhancement parameters with respect to OATP1B3 expression. 
1.2 
Background and Rationale 
1.2.1 Study Disease : 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 217,730 new cases and 32,050 deaths 
due to prostate cancer (CaP) in the United States in 2010 [1]. Despite screening with PSA, 
many patients are diagnosed with advanced stage disease. Androgen deprivation therapy 
(ADT) is the frontline treatment approach for advanced prostate cancer and may be 
accomplished by medical or surgical castration. Although the majority of prostate cancer 
patients initially respond to ADT, disease almost invariably progresses eventually to castration-
resistant prostate cancer. 
1.2.2 Castration Resistant Prostate Cancer (CRPC) 
Normal and cancerous growth of the prostate depends on androgen receptor (AR) expression 
and function. Activation and translocation of the AR by androgens leads to transcriptional 
activity of AR target genes to induce cell growth and maintain homeostasis. In addition, 
signaling of growth factors or transport of hormones may have an important role in 
carcinogenesis and in progression to castrate-resistant disease. Understanding the molecular 
events that lead to castration resistance is essential in developing successful treatments. 
Multiple mechanisms involved in the development of CRPC have been proposed, including 
AR over-expression, AR gene amplification, alteration in AR structure or function, 
intratumoral androgenic steroid synthesis, ligand-independent AR reactivation by growth factor 
pathways, as well as AR-independent mechanisms [2]. While many studies have revolved 
around the AR and its involvement in the androgen signaling axis, relatively little is known 
about the role of testosterone transport and androgen transporters such as OATP1B3 in prostate 
cancer. Emerging data suggest a potential role for these steroid transporters in mediating the 
uptake of androgen into CaP cells and thereby influencing the clinical response to androgen 
suppression. 
1.2.3 OATP1B3 Transports Testosterone and affects clinical outcomes in CaP 
Previous studies have demonstrated that single nucleotide polymorphisms (SNPs) in SLCO 
genes, which encode OATPs, can markedly alter testosterone transport efficiency. Recently, 
the Figg lab has specifically evaluated these SNPs and their association with androgen 


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transport. They showed that a common SLCO1B3 GG/AA haplotype is associated with 
impaired testosterone transport and improved survival in patients with prostatic cancer [3]. The 
study examined (a) the SLCO1B3 genotype in cancer cells as well as the uptake of testosterone 
by cells transfected with genetic variants of SLCO1B3; (b) the expression of OATP1B3 in 
normal prostate, benign prostatic hyperplasia, and prostatic cancer; and (c) the role of 
SLCO1B3 haplotype on the clinical outcome of Caucasian patients with androgen-independent 
prostatic cancer. Cells transfected with wild-type (334T/699G) SLCO1B3, actively transported 
testosterone, whereas its uptake was impaired in cells transfected with a gene carrying both 
334G and 699A single nucleotide polymorphisms. Approximately half of localized prostatic 
cancers over-express OATP1B3 compared with normal or benign hyperplastic tissue; patients 
with SLCO1B3 334GG/699AA haplotype showed longer median survival (8.5 versus 6.4 
years; P = 0.020) and improved survival probability at 10 years (42% versus 23%; P < 0.023) 
than patients carrying TT/AA and TG/GA haplotypes. The common SLCO1B3 GG/AA 
haplotype is associated with impaired testosterone transport and improved survival in patients 
with prostatic cancer [3].  
In a follow-up study, they further showed that the polymorphism that increases testosterone 
transport was associated with a shorter time to androgen independence in patients with prostate 
cancer who are treated with ADT. The study examined the association between this SLCO1B3 
polymorphism and time from ADT to androgen independence, ADT to prostate-specific 
antigen (PSA) nadir and PSA nadir to androgen independence in 68 Caucasian patients with 
advanced prostate cancer with metastatic disease (D2) or biochemical failure without 
metastases (D0) who were treated with ADT. When examined separately, patients with the 
334T allele tended to have a shorter time to androgen independence in the D0 (P = 0.11) and 
D2 (P = 0.18) groups. Combining these groups and stratifying by stage yielded a statistically 
significant shorter time to androgen independence in those patients carrying the T allele (P = 
0.048) [4]. 
Finally, another study by Wright et al found that CRPC metastases demonstrate increased 
expression of SLCO genes vs. primary CaP. SLCO1B3 was highly expressed in CRPC 
metastases vs. untreated CaP (3.6 fold, p=0.0517) and SLCO1B3 SNP rs4149117 (HR 1.76, 
95% CI 1.00 - 3.08) had an increased risk of CaP-specific mortality. In their study, CRPC 
metastases showed increased expression of SLCO genes in comparison with primary prostate 
cancer. Genetic variants of SLCO1B3 and SLCO2B1 found to be associated with CaP-specific 
mortality. Expression and genetic variation of SLCO genes which alter androgen uptake was 
proposed to be important in prostate cancer outcomes and this may allow stratification of 
patients to more aggressive hormonal therapy or earlier incorporation of non-hormonal based 
treatment strategies [5]. 
1.2.4 Rationale 
No currently used imaging method evaluates the status of the OATP1B3 transporter. Such a 
method might be important in stratifying risk factors in patients, both with localized and with 
metastatic disease. 
Eovist® (gadoxetate disodium) is a gadolinium-based contrast agent which was approved by 
the FDA in 2008 [6]. It is indicated for intravenous use in T1-weighted magnetic resonance 
imaging (MRI) of the liver to detect and characterize lesions in adults with known or suspected 
focal liver disease, particularly in the diagnosis of hepatocellular carcinoma (HCC). The agent 


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is taken up by normal hepatocytes and lesions that contain normal hepatocytes (e.g. focal 
nodular hyperplasia). The majority of HCCs do not take up Eovist® and so the agent has 
become useful in the workup of suspected HCC. However, some HCC tumors do take up 
Eovist® and this uptake has been correlated with their OATP1B3 expression [7, 8]. 
The agent is injected intravenously. Because it is a low molecular weight imaging agent it 
rapidly enhances all vascular organs and structures. However, it was not retained by non 
OATP1B3 expressing tissue and so at 20 minutes a correlation was made between OATP1B3 
expressing lesions (persistent enhancement) and non OATP1B3 expressing lesions (washout of 
enhancement).   
Thus, Eovist® will be used in patients with localized and metastatic prostate cancer in order to 
determine if this method is feasible to observe differences in uptake times in prostate cancers 
and whether these differences correlate with OATP1B3 expression in prostate cancer and 
therefore, might serve as a predictive biomarker. 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1 
Eligibility Criteria 
2.1.1 Inclusion Criteria 
2.1.1.1 Subject is 18 years old. 
2.1.1.2 Subjects with clinically localized prostate cancer (outside pathology is acceptable) must 
have image guided biopsy confirmed prostate cancer and sufficient tissue available 
(obtained before or after 20 weeks of Eovist® injection) for OATP1B3 expression.  
2.1.1.3 Subjects with advanced disease who have failed hormone therapy and who have 
sufficient tissue (obtained before or after 20 weeks of Eovist® injection) from a soft 
tissue or metastatic bone lesion (measuring ≥1.5cm in diameter at CT or MRI scan) 
available for OATP1B3 expression.  
or  
2.1.1.4 Subjects, for whom tissue is not available, must have a soft tissue or metastatic bone 
lesion that can be biopsied and be willing to undergo percutaneous biopsy to obtain 
tissue for OATP1B3 expression.  
2.1.1.5 ECOG performance status <2 
2.1.1.6 Serum creatinine within 3 weeks prior to Eovist MRI ≤1.8mg/dl and estimated 
glomerular filtration rate (eGFR) must be >30 ml/min/1.73m2. 
2.1.1.7 Patients must have normal liver function as defined below: 
 total bilirubin< 2X normal institutional limits or >3.0 mg/dl in patients with 
Gilbert’s syndrome 
 AST(SGOT) and ALT(SGPT)<3 X institutional upper limit of normal 
2.1.1.8 Ability of subject to sign a written informed consent document 
2.1.2 Exclusion Criteria 
2.1.2.1 Subjects with known hypersensitivity and allergy to gadolinium contrast agents 


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2.1.2.2 Subjects with any coexisting medical or psychiatric condition that is likely to interfere 
with study procedures and/or results 
2.1.2.3 Subjects with severe claustrophobia unresponsive to oral anxiolytics 
2.1.2.4 Subjects with contraindications to MRI 
2.1.2.5 Subjects weighing >136 kg (weight limit for scanner table) 
2.1.2.6 Subjects with pacemakers, cerebral aneurysm clips, shrapnel injury, or other implanted 
electronic devices or metal not compatible with MRI 
2.1.2.7 Subjects with other medical conditions deemed by the principle investigator (or 
associates) to make the subject ineligible for protocol procedures 
2.1.2.8 Subjects who will have a delay in clinically indicated radiation therapy due to the 
interval between Eovist® MRI imaging and biopsy 
2.2 
Screening Evaluation 
Subjects will be seen in either the UOB, ROB or MOB clinics by members of Dr. Peter Pinto`s, 
Dr. Aradhana Kaushal`s and/or Dr. William Dahut`s teams, respectively.  Conventional 
imaging studies confirming presence of metastatic soft tissue or metastatic bone prostate cancer 
lesions (outside imaging studies are acceptable for study entry) will be reviewed by the 
Molecular Imaging Program staff. 
2.2.1 Screening tests:  
Screening Test must be completed within 21 days prior to the injection of Eovist® 
2.2.1.1 Evaluations: 
 vital signs (BP, HR, RR, & Temperature) 
 clinical laboratory assessments (CBC w/diff, Acute Care Panel, Hepatic Panel, Mineral 
Panel, & PSA) 
 OATP1B3 genotype analysis of blood samples will be done in Dr. William D. Figg`s 
lab; results will not be a part of the study eligibility criteria. 
2.3 
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 faxed to 
301-480-0757. 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. 


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3 
STUDY IMPLEMENTATION 
3.1 
Study Design 
This is an open-label, single-center pilot study. Twenty evaluable subjects will be enrolled, 10 
subjects with localized prostate cancer and 10 subjects with advanced prostate cancer with soft 
tissue or bone involvement. A subject is considered evaluable if he completes pre and post 
Eovist® injection MRI scans and has sufficient tissue for OATP1B3 IHC. 
 Localized disease: 
o If existing pathologic tissue can be linked with confidence to an MRI-defined 
lesion (i.e. pathologic specimen is labeled as to location) then that tissue can be 
used for OATP1B3 expression.  
o Otherwise the tissue obtained during image guided biopsy at NCI will be used 
for OATP1B3 expression testing. 
o Prostatectomy specimens may be a source of tissue if the above sources are not 
available and the patient undergoes prostatectomy. 
 Advanced disease: 
  
o If clinically acquired tissue is not available, the patient must be willing to have a 
percutaneous needle biopsy of a soft tissue lesion or metastatic bone lesion 
(measuring ≥1.5cm in diameter at CT or MRI scan). 
All tissue samples (either biopsy specimens from localized intraprostatic lesions or 
prostatectomy specimens in the localized disease arm or biopsy specimens from the soft tissue 
or metastatic bone lesions in the advanced disease arm) for immunohistochemical (IHC) 
analysis must be acquired within ±20 weeks (assuming no intervening therapy) of Eovist® 
imaging. 
3.1.1 Eovist® enhanced MRI 
MRI will be performed in the Molecular Imaging Clinic. Pre contrast T1, T2 weighted scans 
with or without endorectal coil will be obtained through the prostate gland, bone metastasis or 
soft tissue metastasis (usually a lymph node) selected as the target lesion. Then 0.1 ml/kg 
Eovist® will be administered IV. Scans will be obtained immediately, 10, 20 and 60 minutes 
after injection using the same settings. Contrast enhancement ratios will be determined at each 
time point (Section 3.3). 
3.1.2 OATP1B3 Genotyping 
Genotyping experiments will be performed using genomic DNA isolated from stored frozen 
serum using the QIAmp DNA blood mini-kit (Qiagen, Inc, Valencia, CA). This method has 
been previously utilized for the isolation of genomic DNA in the Figg laboratory [3, 4] and has 
resulted in DNA yields of approximately 50-400 ng/0.5ml of serum. 
Genomic DNA will be amplified using Taq polymerase. Depending on the gene, single 
nucleotide polymorphisms in the CYP450 alleles will be identified using direct sequencing.  
Dr. Figg’s laboratory has previously published methods for genotyping the OATP1B3 alleles 
under study [3, 4]. 


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All biosamples have been given a specimen code number on arrival in the laboratory. All 
further manipulation of the data is performed using the code number. Only named investigators 
will have access to this information, but most information will be stored and analyzed by the 
statistics section of the CCR. 
3.1.3 Pathology 
3.1.3.1 Surgical Pathology 
For the localized disease arm, biopsy specimens obtained from intraprostatic lesions or 
prostatectomy specimens will undergo standard preparation and sectioning in the Laboratory of 
Pathology for pathological diagnosis. The biopsy procedures for the localized disease arm will 
be part of standard of care.  
For the advanced disease arm, biopsy specimens obtained from distant lesions will undergo 
standard preparation and sectioning in the Laboratory of Pathology for pathological diagnosis. 
The biopsy procedure for the advanced disease arm will be research biopsies and will be 
performed under imaging (ultrasound or CT) guidance. 
3.1.4 Immunohistochemistry 
Immunohistochemistry analysis will include exploratory assessment of OATP1B3 expression. 
Analyses will be performed on tumor from all specimens obtained and, will be performed at 
NIH. The Figg Lab has previously published immunofluorescence methods to detect 
OATP1B3 in prostate tissue sections isolated from men with benign prostatic hyperplasia, and 
prostate cancer [3]. The assay was able to distinguish between expressing and non-expressing 
tumors using a primary OATP1B3 antibody purchased from Santa Cruz Biotech. This will be 
used for IHC analysis. Moreover, we are currently developing better methods of detection in 
collaboration with Dr. Scott Lucia (University of Colorado Denver). We are also collaborating 
with Dr. Wooin Lee (University of Kentucky) who has recently published IHC methods using 
antibodies developed in-house. This is a topic which is still under investigation. The scope of 
collaboration with these groups will be limited to data exchange, but will not include sending 
out tissue samples. 


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3.2 
Study Schema 
 
 
 
Figure 1: Study Schemas for localized and advanced disease arms. 
Note: Tissue samples must be obtained within ±20 weeks of Eovist® MRI 


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3.3 
Study Drug Administration/Administration of Eovist® 
Under the supervision of PI or designated personnel, each subject will receive a single IV dose 
of Eovist® by bolus injection at a rate of approximately 2 ml/second at a dose of 0.1ml/kg. The 
injection will be followed by a 10-ml saline flush (sodium chloride IV infusion 0.9% w/v) over 
about10seconds. 
The injection site will be evaluated before and after injection, to assess for the presence of 
signs of local irritation. 
A member of the MIP clinical team will be in attendance during the injection.  In the event of 
an emergency, such as an allergic reaction, immediate treatment will be initiated using 
emergency medication available in the Molecular Imaging Clinic.  If the subject requires 
admission due to the severity of the reaction, the subject will be admitted to UOB, MOB or 
CCMD services for observation as the clinical situation dictates. 
3.4 
Dose Modifications 
If an adverse reaction is noted during the infusion, the infusion will be discontinued 
3.5 
Correlative Studies 
3.5.1 Imaging Correlation 
A volume of interest (VOI) will be drawn over the target lesion in the baseline and in post-
Eovist® injection MR images and the amount of contrast enhancement will be recorded by 
using dedicated image analysis software (MIM 5.4 Software, MIM Software Inc. Cleveland, 
OH, USA). Enhancement ratios [(signal enhancement after enhancement-signal enhancement 
before enhancement)/signal intensity before enhancement] will be calculated on pre and post-
injection T1W MR images.  
3.5.2 Pathologic and Imaging Correlation 
Standard of care biopsy is planned for subjects enrolled in the localized disease arm of this 
study. For patients enrolled in the advanced disease arm, the biopsies will be obtained for 
research purposes. 
In case the new imaging agent shows an unexpected finding, this will be correlated with 
conventional imaging.  The physicians of the patient will use best clinical judgment in 
determining whether a finding will influence the surgical procedure. 
3.5.3 Histological Correlations 
OATP1B3 expression will be confirmed by staining for OATP1B3 in tissue samples on an 
investigational basis. IHC analysis will be conducted by one NCI pathologist and will be based 
on grade of positivity (0 (no staining), 1 (weak staining), 2 (moderate staining) or 3 (strong 
staining)). 
3.5.4 Safety Assessments 
Safety assessments will obtained during the course of the study are summarized in the Study 
Calendar (Section 3.6). 


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3.6 
Study Calendar 
The timing of study events in the following descriptions is relative to the administration of 
EOVIST®. 
Procedure 
Screeninga Baselineb 
MR imaging 
Scheduled 
Post-MRIc 
 
 
 
Just prior 
to MRI 
Pre-
injection 
MRI scan 
Post 
injection 
MRI scan 
 
Informed consent 
X 
 
 
 
 
 
Study entry criteria 
X 
 
 
 
 
 
Demographic 
information 
X 
 
 
 
 
 
Medical history and 
concurrent diseases 
X 
 
 
 
 
 
Prior/concomitant 
medications 
X 
 
 
 
 
 
Injection site 
monitoring 
 
 
 
X 
Xd 
X 
Vital signs 
X 
X 
 
 
Xe 
 
Acute Care Panel, 
Hepatic Panel, 
Mineral Panel, PSA, 
& CBC 
Xf 
 
 
 
 
 
OATP1B3 Genotype 
analysis 
Xg 
 
 
 
 
 
Biopsy specimen 
available for 
OATP1B3 
expression 
Xh, i 
 
 
 
 
 
Intravenous line 
started 
 
 
X 
 
 
 
Eovist® injection 
 
 
 
X 
 
 
Adverse Event 
Monitoring 
 
 
X 
X 
X 
X 
MR Imaging 
 
 
 
X 
Xj 
 
Biopsy Procedure 
 
 
 
 
 
Xk, l 
Prostatectomy 
 
 
 
 
 
Xm 
OATP expression 
and Comparative 
Analyses 
 
 
 
 
 
X 
a: Within 21 days of administrations of Eovist® 
b: The day of MR imaging until just prior to administration of Eovist ® 


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c. Timing of events is relative to administration of Eovist® 
d: 5 minutes post-Eovist® injection 
e: At the end of all scanning 
f: Clinical blood sample assessments must be performed within 21 days prior to administration of 
Eovist®. 
g: Will be performed at Dr. William D. Figg`s Lab. 
h: For the localized disease arm, existing pathologic tissue (obtained <20 weeks before Eovist MRI) will 
be screened to see if it can be linked to MRI visible lesion in the patient candidate for Eovist MRI. 
Otherwise the tissue obtained from image guided biopsy (standard of care) at NCI will be used for 
OATP1B3 expression. 
i: For the advanced disease arm, availability of the previously (<20 weeks) obtained clinically acquired 
tissue will be checked. 
j: Immediately, 10, 20, & 60  minutes post-Eovist® injection 
k: To be conducted within <20 weeks after Eovist® enhanced MRI 
l: This applies for the advanced disease arm and will be conducted from a soft tissue or metastatic bone  
lesion (measuring ≥1.5cm in diameter). 
m: This applies for the localized disease arm and will serve as a source of tissue only if previously 
acquired biopsy (confidently linked to an MRI visible lesion) or image guided standard of care biopsy at 
NCI will not be available. 
3.6.1 Study Periods 
3.6.1.1 Screening Period 
A screening visit will be performed within 21 days before administration of Eovist®.  Subjects 
will be permitted to continue taking any routine or necessary medication. 
All subjects must satisfy all the eligibility criteria listed in Section 2.1.  Signed and dated 
informed consent must be obtained from all subjects before any study-specific procedures are 
performed. 
The following data will be collected: 
 Date of birth 
 Weight 
 Height 
 Prior and concurrent medications 
 Medical history and concurrent diseases 
 Results of screening tests: laboratory tests 
Personal data (including contact information) will be collected with the subject’s permission 
and only to the extent that is necessary for the purposes of the study.  Blood samples for 
laboratory tests will be drawn. Vital signs (i.e., systolic and diastolic blood pressure, heart rate, 
body temperature, and respiration rate) will be recorded.    
3.6.1.2 Baseline Period 
The baseline period is defined as the day of MR imaging until just prior to administration of 
Eovist®.  At baseline, concomitant medication and pre-administration events will be recorded.  


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A cannula (or indwelling catheter) will be placed preferably into an antecubital vein for blood 
sampling and imaging agent administration.  Blood samples for serum biochemistry and 
hematology will be drawn. Vital signs (i.e., systolic and diastolic blood pressure, heart rate, 
body temperature, and respiration rate) will be recorded. 
If the screening clinical blood sample assessments are performed within 48 hours of 
administration of Eovist®, they do not need to be repeated.  
3.6.1.3 MR Imaging Period 
Prior to entering the MRI 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. An 
endorectal coil will be used for localized disease arm. 
The following scans will be obtained: 
 Scout view of the pelvis to check positioning of the cardiac coil. 
 T1 weighted MRI of abdomen and pelvis. 
 T2 weighted MRI of abdomen and 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-injection MRI scan, patient will have the Eovist® injection as 
detailed above in section 3.3. The patient will be assessed for adverse events 15 minutes post- 
Eovist® Injection and if they are stable, the same MR imaging protocol (except for the scout 
view) specified above will be performed immediately after injection and at approximately 10th, 
20th and 60th minute time points after injection with the same MRI set up.  
Following imaging acquisition, the data will be transferred to the clinical PACS system for 
storage. 
3.6.1.4 Post-Eovist® Enhanced MR Imaging Period 
A final set of vital signs and AE assessment will be performed at the end of the 60 minute MRI 
scan. 
Within 20 weeks of the Eovist® enhanced MRI the biopsy procedure will be performed. 
3.6.1.5 Clinical Laboratory Evaluations 
The clinical laboratory variables assessed in this study are displayed in Table 1; they will be 
measured at the NIH Clinical Center laboratory.  
Table 1 Clinical Laboratory Variables 
Serum Biochemistry 
Hematology 


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Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Bilirubin (total, direct) 
Calcium 
Chloride 
Creatinine 
Glucose 
Potassium 
Sodium 
Urea nitrogen 
PSA 
Hematocrit 
Hemoglobin 
Platelet count 
Red blood cell count 
White blood cell (WBC) count 
Blood samples will be obtained for assessment of serum biochemistry and hematology 
parameters as described in the Study Calendar (Section 3.6). The maximum amount of blood 
taken for these tests will not be more than 60 ml. 
Interpretation and follow-up of abnormal laboratory test results should be conducted in 
conjunction with the clinical situation of the subject and in consultation with the referring 
physician.   
3.6.1.6 Vital Signs 
Vital signs will be measured at various pre- and post-injection time points described in the 
Study Calendar. Vital sign parameters include measurements of systolic and diastolic BP, heart 
rate, temperature and respiratory rate. 
The interpretation and follow-up of abnormal vital signs results should be conducted on a case 
by case basis in conjunction with the individual clinical situation. 
3.6.1.7 Injection Site Monitoring 
Injection site monitoring will be performed prior to administration of the imaging agent and at 
the 5th minute post-injection described in the Study Calendar (Section 3.6). Any abnormal 
findings during this period will be recorded as AEs on the research record. Abnormal injection 
site findings include, but are not limited to, pharmaceutical extravasation, bleeding, hematoma, 
redness and infection. 
Any abnormal finding that is new or represents a worsening from baseline is an AE. Once AE 
notification is decided upon, investigators are required to follow the procedure described for 
AE notification and document the abnormal finding in the subject’s research record. 
3.6.1.8 Pre-administration events 
The presence of any pre-administration event (baseline signs and symptoms present just before 
Eovist® administration) will be recorded in C3D  
The following information will also be recorded: 


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 The date and time of evaluation 
 The onset time 
 The resolution time or duration 
 Action taken 
 Status of symptom 
 Intensity 
3.7 
Surgical Guidelines 
As part of their standard of care for their disease, subjects will have biopsy within 20 weeks of 
Eovist® enhanced MRI. Pathologic specimens will be obtained for histological assessment.  
Further details are provided in Section 3.1.4. 
In the event that the Eovist® enhanced MRI scan demonstrates an unexpected finding, it will 
be correlated with conventional imaging. While Eovist® enhanced MRI findings will not be 
used to direct therapy, the referring physician(s) will be made aware of any such findings, and 
may perform additional tests to clarify findings. 
3.8 
Radiation Therapy Guidelines 
The patient should not undergo radiation therapy to the target lesion between biopsy and 
Eovist® MRI imaging. However, clinically indicated radiation therapy cannot be delayed by 
the biopsy after Eovist® enhanced MRI. 
3.9 
Off-Study Criteria 
Patients will be taken off study once all study procedures are complete.  In cases where a 
subject withdraws or is withdrawn from the study after administration of Eovist® and before 
biopsy is performed, a replacement subject will be enrolled. 
Should a subject withdraw after administration of Eovist®, or should the investigators decide 
to withdraw the subject, all efforts will be made to complete and report the protocol-stipulated 
observations up to the time of withdrawal as thoroughly as possible. A final evaluation at the 
time of the subject’s withdrawal should be made and an explanation given of why the subject is 
withdrawing or being withdrawn from the study. The reason and date and time of withdrawal 
must be recorded. If the reason for withdrawal is a clinical AE, monitoring will continue until 
the outcome is established. 
3.9.1 Criteria for Removal from Protocol 
 Investigators have the right to withdraw subjects from the study in the event of illness, 
AEs, or other reasons concerning the health or well-being of the subject, or in the case 
of lack of co-operation. 
 Subject completes Eovist® enhanced MRI and has biopsy of the target lesion 
 Patient requests to be taken off study 
 Patient non-compliance with protocol guidelines 


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 Unacceptable treatment related toxicity as described in section 10.2.2 
Patient may not be taken off study until unacceptable toxicities have stabilized or resolved. 
3.9.1.1 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 
faxed to 301-480-0757. 
4 
CONCOMITANT MEDICATION/MEASURES 
MRI contrast may be lessened by the following concomitant medications (OATP1B3 
inhibitors) 
 Select antibiotics (rifampicin, penicillin, ceftriaxone, cefmetazole, cefoperazone, and 
cefotaxime) 
 Cyclosporin A 
 Docetaxel / Paclitaxel 
 Digoxin 
 Fexofenadine 
 Ibuprofen 
 Imatinib 
 Irinotecan 
 Methotrexate 
Any non-essential medications on the above list should be put ‘on-hold’ prior to the MRI for 
three days. Antibiotics should be finished before the MRI. If there is an essential medication 
that cannot be substituted then it will be noted but the patient will still be eligible for the study. 
5 
DATA COLLECTION AND EVALUATION 
5.1 
Data Collection 
5.1.1 Clinical Data 
All data will be kept secure. Personal identifiers will not be used when collecting and storing 
data. An enrollment log will be maintained in the regulatory binder/file which is the only 
location of personal identifiers with unique subject identification number. 
Clinical data including summary and demographic data will be collected and entered into NCI 
CCR Database, C3D. Adverse events occurring during any scanning session will be recorded. 
Adverse events which are designated possibly, probably or definitely related to Eovist® will 
also be recorded. 
Imaging data will include storage of the reconstructed images and image derived parameters on 
a secure, password protected lab imaging database. The lab imaging database will be stored 


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and maintained in the Molecular Imaging Program facilities. Personal identifiers will not be 
used when storing data. 
Non-Anonymized images may also be stored in the clinical center PACS. 
5.1.2 Safety Data 
The following safety data will be collected and evaluated according to the Study Calendar 
(Section 3.6): 
 Clinical laboratory variables: serum biochemistry and hematology 
 Injection site monitoring 
 Pre-administration events (baseline signs and symptoms) 
 AEs 
SAEs will be recorded if they occurred as follows: 
 After a subject first received Eovist® and throughout the subjects follow-up period, 
 During the subject’s follow up period, and for which a causal relationship to Eovist® 
cannot be ruled out. 
Interpretation and follow-up of abnormal results will be done on a case by case basis in 
conjunction with the individual clinical situation. Any clinically significant abnormal finding, 
or change in one that represents a worsening from baseline, is an AE. Once a decision is 
reached to report a finding as an AE, the investigator is required to follow the procedure 
described for AE notification.  
5.1.3 Imaging Data 
Extracted imaging data include: 
(1) All image data will be stored on a secure server, with access limited to credentialed 
users. This will permit flexible numeric raw data extraction for quantitative analysis 
and creation of summary data reports. 
(2) Anonomymized image data from this study will be stored in a secure database that it is 
administered by the Cancer Imaging Program, NCI. The database is password protected 
and access is only given to qualifying collaborators. 
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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6 
BIOSPECIMEN COLLECTION  
6.1 
Tissue Samples 
All tissue specimens (slide specimens) should be obtained as specified in the protocol and will 
be barcoded and labeled as described in the following sections. Tissue samples will be stained 
for immunohistochemistry analysis of OATP1B3 expression in NIH (please see section 3.5.3).  
In patients with localized disease, tissue can be obtained from image guided biopsies or from 
prostatectomy specimens. 
In patients with advanced disease, tissue will be obtained from a target lesion (measuring 
≥1.5cm in diameter at CT or MRI scan) by biopsy either incidental to this study or obtained 
specifically for this study. 
6.2 
Blood Samples 
Blood samples will be collected for screening and on-study clinical laboratory safety 
assessments.  All blood samples will be processed and handled in accordance with standard 
laboratory procedures.  All samples except for the one obtained for OATP1B3 genotyping will 
be analyzed at the NCI Clinical Center laboratory. The peripheral blood sample obtained for 
OATP1B3 genotyping will be analyzed in Dr. William D. Figg`s Lab. Peripheral blood for 
DNA extraction will be collected in a 10-ml K2EDTA vacutainer. The vacutainer will be 
placed on wet ice after draw store in a 4C refrigerator until pick-up. The research nurse 
(Yolanda McKinney) will record the date and time of draw on the blood tube label. 
Please immediately page 102-11964 for pick-up. Contact the Clinical Pharmacology Program 
(CPP) processing group in 10/5A09 at 301-594-6131 or 301-402-3622 with any questions. 
6.3 
Pathology Specimens 
6.3.1 Surgical Pathology 
Specimens will be obtained from biopsy as described in Section 3.1.2 and mounted on glass 
slides.  Slides will be labeled with study number, subject number, sampling date.  Slide 
specimens will be stained to assess tumor tissue will be performed by one pathologist.  IHC 
analysis will be conducted on slides to assess the expression of OATP1B3 (please see section 
3.5.3).  
6.4 
Sample Storage, Tracking and Disposition 
6.4.1 Sample Processing and Storage: 
Each patient research tissue sample will be assigned a unique patient identifier and relevant 
sample characteristics (such as timing of sample collection, treatment cycle and day identifiers) 
will be recorded. The location of all tissue samples will be carefully tracked in the secure 
database.  All stored tissue samples will be coded and no identifying patient information will 
be on placed on sample containers. Stored tissue samples will be kept in freezers / refrigerators 
or secure containers located in the NCI research laboratories or in the laboratories of 
collaborators. 
For the blood samples obtained for genotyping, peripheral blood samples sent to the Clinical 
Pharmacology Program (CPP) will be barcoded, with data entered and stored in the Patient 


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Sample Data Management System (PSDMS) utilized by the CPP. This is a secure program, 
with access to PSDMS limited to defined CPP personnel, who are issued individual user 
accounts. Installation of PSDMS is limited to computers specified by Dr. Figg. These 
computers all have a password restricted login screen. All CPP personnel with access to patient 
information annually complete the NIH online Protection of Human Subjects course.  
PSDMS creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to patients without PSDMS access. The data recorded for each sample includes the patient 
ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, as 
well as box and freezer location. Patient demographics associated with the clinical center 
patient number are provided in the system. For each sample, there are notes associated with the 
processing method (delay in sample processing, storage conditions on the ward, etc.). 
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80C 
according to stability requirements.  These freezers are located onsite in the CPP and offsite at 
NCI Frederick Central Repository Services (Fisher Bioservices) in Frederick, MD. Visitors to 
the laboratory are required to be accompanied by laboratory staff at all times.  
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in PSDMS. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol) and that any unused 
samples must be returned to the CPP. It is the responsibility of the NCI Principal Investigator 
to ensure that the samples requested are being used in a manner consistent with IRB approval. 
Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following IRB approval of an additional protocol, granting 
the rights to use the material.  
If, at any time, a patient withdraws from the study and does not wish for their existing samples 
to be utilized, the individual must provide a written request. Following receipt of this request, 
the samples will be destroyed (or returned to the patient, if so requested), and reported as such 
to the IRB. Any samples lost (in transit or by a researcher) or destroyed due to unknown 
sample integrity (i.e. broken freezer allows for extensive sample thawing, etc.) will be reported 
as such to the IRB. 
Sample barcodes are linked to patient demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of 
the PSDMS. It is critical that the sample remains linked to patient information such as race, 
age, dates of diagnosis and death, and histological information about the tumor, in order to 
correlate genotype with these variables. 
6.4.2 Timeframe for research studies  
Samples will be stored until requested by an authorized researcher(s). All researchers are 
required to use the samples for research purposes associated with this trial (as per the NCI IRB 
approved protocol). Subjects will be given the option of consenting to future use of their 
research samples per the informed consent process with their option declared in the consent 
document. Samples from those patients who consent to this will be stored permanently. 
However, these samples will be used only for research studies on active NCI IRB approved 
protocols covered by a valid informed consent document. Samples will be destroyed at the 


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completion of the study from those subjects who decline future use of their samples. Once 
primary research objectives for the protocol are achieved, intramural researchers can request 
access to remaining samples provided they have an IRB approved protocol and patient consent. 
Any unused samples must be returned to the NCI laboratories as appropriate. The PI will report 
destroyed samples to the IRB if samples become unsalvageable because of environmental 
factors (e.g. broken freezer or lack of dry ice in a shipping container) or if samples are 
destroyed because a patient withdraws consent. Samples will also be reported as lost if they are 
lost in transit between facilities or misplaced by a researcher. Any freezer problems, lost 
samples or other problems associated with samples will be reported to the IRB, the NCI 
Clinical Director, and the office of the CCR, NCI. 
7 
STATISTICAL CONSIDERATIONS 
7.1 
Study Populations 
25 evaluable patients will be included in this trial with an accrual rate of 1-2 patients a month. 
Therefore, it is expected that this study enrollment will be completed within 1.5 years and full 
study goals within 2.5 years. We plan to enroll 25 evaluable patients (10 in arm 1 and 15 in 
arm 2). 
7.2 
Subject Characteristics 
Subject characteristics will be summarized with the following information: 
 Number of subjects enrolled 
 Number of subjects included in the safety analysis 
 Number of subjects included in the efficacy analysis 
 Number of subjects withdrawn from the study and the reason for withdrawal 
Demographic information (age, height, weight, and body mass index) will be summarized 
using descriptive statistics.  Race will be summarized by counts and percents. 
Medical histories will be summarized by counts and percents. Concurrent medications will be 
recorded, coded and grouped by primary and secondary classes, if applicable. 
7.3 
Efficacy Analysis 
7.3.1 Primary Efficacy Analysis 
The primary objective of the study is to evaluate the uptake and retention of Eovist® in 
prostate cancers measured by the change of MRI parameter values between pre- and post- 
injection (section 3.5.1). Log-transformed MRI parameter values between pre- and post-
injection will be compared by the paired t-test. If the distribution of log-transformed MRI 
parameter values is skewed, nonparametric paired Wilcoxon signed-rank test will be used for 
comparison. 
7.3.2 Secondary Efficacy Analysis 
The secondary objective of the study is to evaluate Eovist® MR parameters with respect to 
OATP1B3 lesion expression.  


Abbreviated Title: Eovist® MRI of prostate cancer 
Version Date: 05/04/2015 
 
- 26 - 
Imaging will be performed on 2 subgroups of prostate cancer patients. Subgroup 1 consists of 
early stage (non-metastatic) patients, subgroup 2 late stage (confirmed metastatic with prior 
hormonal ablation therapy) patients. It is expected that OATP1B3 expression is higher in late 
stage patients (subgroup 2) than in early stage patients. 
For patients in subgroup 2, expression of OATP1B3 will be determined in soft tissue or bone 
lesions taken from biopsy and will be correlated with MRI signal change by both Pearson and 
Spearman correlation coefficient. 
As OATP1B3 SNPs also alter androgen uptake, affecting outcome of androgen deprivation 
therapy (ADT) [3, 4], genotype will also be compared to progression-free survival on ADT. 
Genotypes will be compared to these endpoints using the chi-squared and/or Fisher’s exact test, 
or the log-rank test as appropriate. 
7.4 
Sample Size Determination 
Sample size and power calculation is based on comparing signal change between pre- and post-
injection in each subgroup separately. Based on a prior study on liver cancer patients, up to 3-
fold mean signal change may be detected and the standard deviation of log-transformed signal 
ratio is approximately 0.25. With 10 evaluable patients in subgroup 2 (late stage), there is more 
than 95% power to detect a 2-fold mean signal change between pre- and post-injection at 5% 
significance level. For the first subgroup, OATP1B3 expression is likely lower and hence 
smaller signal change is expected. With 10 evaluable patients in each of these two subgroups, 
there is 83% power to detect a minimal 1.2 fold mean signal change. Higher power may be 
achieved if each patient has multiple lesions. Signal changes of multiple lesions from the 
sample patients will be averaged, and the comparison is based on the paired t-test using log-
transformed signal values on a subject basis.  
8 
HUMAN SUBJECTS PROTECTION 
8.1 
Rationale for Subject Selection 
The patient population in whom this disease occurs is adult males. All ethnic groups/ race 
categories would be represented as they are represented in the disease as a whole. Cognitively 
impaired individuals will not be included in this study if they are unable to understand the 
informed consent. Physically impaired persons who otherwise satisfy eligibility criteria will be 
included in this study. This study is considered more than minimal risk to subjects and no 
direct benefits to the patient are expected. We anticipate that a thorough discussion of the study 
at the time informed consent is obtained will minimize any susceptibility to undue influences 
and unnecessary risks to research subjects. 
8.2 
Participation of Children 
Prostate cancer is not seen in children. Thus, we will not include children in this study. 
8.3 
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.   


Abbreviated Title: Eovist® MRI of prostate cancer 
Version Date: 05/04/2015 
 
- 27 - 
The risks for participating are also minimal. Because the risks of Eovist® injection and MRI 
are uncommon, we anticipate a low rate of adverse events at the FDA-approved, low-dose level 
used in this study. 
8.4 
Risks/Benefits Analysis 
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 Eovist® injection 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. The scan will give valuable 
information about the OATP1B3 status of prostate tumors and could lead to Improvements in 
prostate cancer therapies targeted to OATP1B3. Adults who are or may be unable to consent 
are excluded. 
8.5 
Consent and Assent Process and Documentation 
The subject will be informed of the study by a member of the study team. Written and oral 
information about the study in a language understandable by the subject will be given to all 
subjects. The study will be explained in detail and the consent form and protocol (if requested) 
will be provided to the subject to take home (if desired) for consideration. If the subject has any 
questions they will be answered at the time of initial protocol discussion or later by telephone. 
Each subject’s willingness to participate in the study will be documented in a signed and dated 
informed consent form before any procedures or assessments are done and after the aims, 
methods, anticipated benefits, potential hazards, and insurance arrangements in force are 
explained. It will also be explained to the subjects that they are free to refuse entry into the 
study and free to withdraw from the study at any time without prejudice to future treatment. 
The informed consent process will be documented in the subject's medical record and the 
investigator will sign, and date the informed consent form after the subject and/or legal 
representative has signed and dated it. The investigator(s) will keep the original consent forms 
and copies will be given to the subjects. Informed consent may be obtained from the patient by 
the PI, an associate PI or any clinical designee credentialed to obtain informed consent for any 
procedure.  
9 SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN 
9.1 
Definitions 
9.1.1 Adverse Events 
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 requiring treatment. For this 
study, AEs will include events reported by the patient, as well as new onset abnormal findings 
on physical examination or laboratory evaluation. A new illness, symptom, sign or laboratory 
abnormality outside the range of normal limits or greater than 50% increase from baseline 
value if the baseline is above the upper limit of normal or worsening of a pre-existing condition 
or abnormality is considered an AE.  


Abbreviated Title: Eovist® MRI of prostate cancer 
Version Date: 05/04/2015 
 
- 28 - 
All AEs, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until satisfactory resolution. AEs should be reported up 
to 30 days following the last dose of study drug.  
An abnormal laboratory value will be considered an AE if the laboratory abnormality is 
characterized by any of the following: 
 
Results in discontinuation from the study 
 
Is associated with clinical signs or symptoms  
 
Requires treatment or any other therapeutic intervention 
 
Is associated with death or another serious adverse event, including hospitalization.  
 
Is judged by the Investigator to be of significant clinical Impact 
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome. 
9.1.2 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. 
9.1.3 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. 
9.1.4 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. 
9.1.5 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 


Abbreviated Title: Eovist® MRI of prostate cancer 
Version Date: 05/04/2015 
 
- 29 - 
 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. 
9.1.6 Disability 
A substantial disruption of a person’s ability to conduct normal life functions. 
9.1.7 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. 
9.1.8 Protocol Deviation (NIH Definition) 
Any change, divergence, or departure from the IRB approved research protocol.   
9.1.9 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. 
9.1.10 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. 
9.2 
NCI-IRB Reporting 
9.2.1 NCI-IRB Expedited Reporting of Unanticipated Problems and Deaths 
The Protocol PI will report to the NCI-IRB: 
 All deaths, except deaths due to progressive disease  
 All Protocol Deviations 


Abbreviated Title: Eovist® MRI of prostate cancer 
Version Date: 05/04/2015 
 
- 30 - 
 All Unanticipated Problems 
 All serious non-compliance 
Reports must be received by the NCI-IRB within 7 working days of PI awareness via iRIS. 
9.2.2 NCI-IRB Requirements for PI Reporting of Adverse Events at Continuing Review 
The protocol PI will report to the NCI-IRB:  
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.  
9.3 
Data and Safety Monitoring Plan 
9.3.1 Principal Investigator/Research Team 
The Principal Investigator and Research Nurse will monitor the study for AEs. 
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.  
The principal investigator reserves the right to terminate the study on safety grounds. If 3 study 
subjects experience ≥ grade 2 Eovist®-related SAEs then the study will be terminated. Before 
terminating the study, the investigator will ensure that a review of the overall risk/benefit 
analysis confirms the balance to be no longer acceptable. Should termination be necessary, the 
investigator will arrange the relevant procedures, which will include informing the IRB, and 
other relevant local and national authorities. On termination of the study, the investigator will 
assure that adequate consideration is given to the protection of enrolled subjects’ interests. 
Termination of the study will be considered in the event of significant safety findings occurring 
at any time during the performance of the study. 
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 and 
violations will be immediately reported to the IRB using iRIS.  
The principal investigator will review adverse event and response 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. 


Abbreviated Title: Eovist® MRI of prostate cancer 
Version Date: 05/04/2015 
 
- 31 - 
10 PHARMACEUTICAL INFORMATION 
10.1 Eovist® Source 
Eovist® is an FDA approved pharmaceutical and it is commercially available from Bayer 
Pharmaceuticals, Inc. 
10.2 Toxicity 
10.2.1 Pharmacology and Toxicology in Animals 
A dose-related increase in QT interval corrected for heart rate (QTc) which was resolved by 30 
minutes post dosing was observed in dogs when given a single dose of Eovist®. The increase 
was noted when given in doses equal to or greater than 0.1 mmol/kg (2.2 times the human 
dose). Maximum increase in QTcF was equal to or less than 20 ms at doses up to 0.5 mmol/kg 
(11 times the human dose). A gait disturbance was observed in 1 of 3 mice when given 
Eovist® at a dose of approximately 1.1 mmol/kg (3.6 times the human dose); the disturbance 
occurred at 30 minutes post dosing and resolved at 4 hours post dosing. 
10.2.2 Toxicity in Humans 
Toxicities are not anticipated in this study.  In the event that a patient experiences an allergic 
reaction, or toxicity greater than grade 2 during the Eovist® injection, the injection will be 
stopped immediately and standard supportive measures instituted. No further Eovist® will be 
administered. 
Overall, 4.3% of subjects reported one or more adverse reactions during a follow-up period that 
for most subjects, extended 24 hours after Eovist® administration. The reported AEs of 
Eovist® were feeling hot (0.9%), nausea (0.6%), headache (0.5%), injection site reactions, the 
reported serious reaction rate is less than 0.5% [6].  
Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis 
(NSF) among patients with impaired elimination of the drugs. The GBCA-associated NSF risk 
appears highest for patients with chronic, severe kidney disease (GFR <30 mL/min/1.73m2) as 
well as patients with acute kidney injury. The risk appears lower for patients with chronic, 
moderate kidney disease (GFR 30–59 mL/min/1.73m2) and little, if any, for patients with 
chronic, mild kidney disease (GFR 60-89 mL/min/1.73m2). NSF may result in fatal or 
debilitating fibrosis affecting the skin, muscle and internal organs [6]. 
Anaphylactoid and anaphylactic reactions with cardiovascular, respiratory and cutaneous 
manifestations, ranging from mild to severe reactions, including shock have uncommonly 
occurred following Eovist® administration. Most hypersensitivity reactions to Eovist® have 
occurred within half an hour after administration. Delayed reactions (hours up to several days) 
may occur [6]. 
10.2.3 Formulation and Preparation 
Eovist® contains the active pharmaceutical ingredient gadoxetate disodium (Gd-EOB-DTPA), 
which is designated chemically as (4S)-4-(4-Ethoxybenzyl)-3,6,9-tris(carboxylatomethyl)-
3,6,9-triazaundecanedioic acid, gadolinium complex, disodium salt with a molecular weight of 
725.72 and an empirical formula of GdC23H28N3O11Na2. 


Abbreviated Title: Eovist® MRI of prostate cancer 
Version Date: 05/04/2015 
 
- 32 - 
Each mL of Eovist® contains 181.43 mg of gadoxetate disodium (equivalent to 0.25 mol/L 
gadoxetate disodium) and the excipients caloxetate trisodium, trometamol, hydrochloric acid 
and/or sodium hydroxide (for pH adjustment), and water for injection.  Eovist® contains no 
antimicrobial preservative. Eovist® has a pH of 6.8 to 8. 
10.2.4 Stability and Storage 
The intact vials remain clinically acceptable until the expiration date indicated on the vial. 
Eovist® should be stored at temperatures between 20–25°C (68–77°F); excursions permitted to 
15–30° C. 
10.2.5 Administration Procedures 
Eovist® is usually directly injected intravenous through an intravenous line at a rate of 2 
mL/second. 
10.2.5.1 Supply and Packaging 
Eovist® is supplied in single-dose, rubber stoppered vials containing 181.43 mg/mL of 
gadoxetate disodium, equivalent to 0.25mmol/mL, in the following sizes: 10 mL single-dose vials 
filled with 10 mL, in individual cartons, boxes of 20 NDC 50419-320-01.  No additional 
preparation is necessary. 
10.2.6 Incompatibilities 
Anionic drugs primarily secreted into the bile (such as rifampicin) may reduce the hepatic 
contrast enhancement and the biliary excretion of Eovist®. 
The chemical structure of Eovist® is shown in Figure 2 below. 
Figure 2 Structure of Eovist® 
 
Molecular formula:  GdC23H28N3O11Na2 
Molecular weight:  
 725.72


Abbreviated Title: Eovist® MRI of prostate cancer 
Version Date: 05/04/2015 
 
- 33 - 
 
11 REFERENCES 
1. 
Jemal, A., et al., Cancer statistics, 2010. CA Cancer J Clin, 2010. 60(5): p. 277-300. 
2. 
Craft, N. and C.L. Sawyers, Mechanistic concepts in androgen-dependence of prostate 
cancer. Cancer Metastasis Rev, 1998. 17(4): p. 421-7. 
3. 
Hamada, A., et al., Effect of SLCO1B3 haplotype on testosterone transport and clinical 
outcome in caucasian patients with androgen-independent prostatic cancer. Clin 
Cancer Res, 2008. 14(11): p. 3312-8. 
4. 
Sharifi, N., et al., A polymorphism in a transporter of testosterone is a determinant of 
androgen independence in prostate cancer. BJU Int, 2008. 102(5): p. 617-21. 
5. 
Wright, J.L., et al., Expression of SLCO transport genes in castration-resistant prostate 
cancer and impact of genetic variation in SLCO1B3 and SLCO2B1 on prostate cancer 
outcomes. Cancer Epidemiol Biomarkers Prev, 2011. 20(4): p. 619-27. 
6. 
EOVIST (Gadoxetate Disodium) Injection for intravenous use. PRESCRIBING 
INFORMATION. 2010 December 2010 [cited 2014 July 29, 2014]; December 
2010:[Available from: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022090s004lbl.pdf  
7. 
Leonhardt, M., et al., Hepatic uptake of the magnetic resonance imaging contrast agent 
Gd-EOB-DTPA: role of human organic anion transporters. Drug Metab Dispos, 2010. 
38(7): p. 1024-8. 
8. 
Narita, M., et al., Expression of OATP1B3 determines uptake of Gd-EOB-DTPA in 
hepatocellular carcinoma. J Gastroenterol, 2009. 44(7): p. 793-8. 
 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
INSTITUTE: 
National Cancer Institute 
STUDY NUMBER: 
13-C-0145 
PRINCIPAL INVESTIGATOR: 
Ismail Baris Turkbey, M.D. 
STUDY TITLE:  
Pilot Study of Eovist® (Gadoxetate) Enhanced MRI for the Detection of Prostate Cancer 
 
Continuing Review Approved by the IRB on 01/12/15 
Amendment Approved by the IRB on 05/12/15 (D)             
 
            Date Posted to Web: 05/13/15 
Standard 
 
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.   
Why is this study being done?  
Prostate cancer is the most common cancer type among men. Although some prostate cancers 
respond to hormonal therapy, there are cellular characteristics of other prostate cancers that cause 
it not to respond as well to hormonal therapy. The purpose of this study is to test Eovist, an 
imaging agent, to see if it is helpful in identifying these different types of prostate cancers using 
MRI scans.   
Eovist (gadoxetate disodium) is a magnetic resonance imaging (MRI) contrast agent that was 
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) 
 
 


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:   13-C-0145 
CONTINUATION: page 2 of 9 pages 
 
approved by the FDA to use in MRI of the liver to detect and characterize lesions (damages in 
tissues) in adults with known or suspected liver disease. Eovist’s uptake in liver lesions is 
recently shown to be linked with presence of a biomarker called OATP1B3. A biomarker is 
molecule that can be used as an indicator of a particular disease.  This biomarker is an abundant 
molecule in prostate cancers which are resistant to hormonal therapy. So use of Eovist to detect 
the presence of OATP1B3 in the prostate cancer in this protocol is experimental. As a long term 
scientific goal we hope to find out if Eovist will be predictive for hormonal therapy resistance. 
Why are you being asked to take part in this study? 
You are being invited to take part in this research study because you have prostate cancer and 
will have surgery to remove your prostate or will have biopsy of your tumor which is located 
outside your prostate. 
How many people will take part in this study?  
Up to 25 people will be included in this study. 
Description of Research Study 
What will happen if you take part in this research study?   
Before you sign this document, you will have several procedures to determine if you are eligible 
for this study. Several vials of blood will be drawn for a panel of tests. You will also have a 
physical exam and answer questions about your medical history and current medications. Your 
doctor will review all the eligibility requirements to ensure you meet all the criteria before you 
enter the study. If you are determined to be eligible for this study, you will then be scheduled to 
return for the study injection and imaging scans. 
Imaging Studies (Scans): 
MRI Imaging: 
A standard MRI 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 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 placed in your arm before your MRI scan. 
The agent called Eovist will be injected into your arm through the IV. The MRI imaging will be 
performed just before the Eovist agent is injected into your arm. MRI imaging will also be 
performed 10, 20 and 60 minutes after the Eovist agent is injected into your arm. You will 
receive more information about your MRI scan when you visit the Molecular Imaging Clinic. 
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. 
Biopsy: 
If you have undergone surgery, your prostate will be studied for tumor cells. This biopsy 
procedure will be standard of care. If you do not undergo surgery, some tissue from one of your 
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 
 
 


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:   13-C-0145 
CONTINUATION: page 3 of 9 pages 
 
tumors located outside the prostate gland may be removed by a needle if that tumor has not been 
biopsied before. This biopsy procedure will not be performed as standard of care but as a 
separate additional research biopsy.  
 
The tissue collected during your biopsy will be evaluated at NIH just as it would be if you were 
not participating in this trial. Your tissue will be evaluated for biomarkers that predict uptake of 
Eovist by your tumor. 
Birth Control 
If your partner can become pregnant, you or your partner will need to practice an effective form 
of birth control during the time you are participating in this protocol. If you think that your 
partner is pregnant, you should tell your study doctor or nurse at once.   
Effective forms of birth control include:  
• abstinence  
• intrauterine device (IUD) 
• hormonal (birth control pills, injections, or implants) 
• tubal ligation 
• vasectomy 
Alternative Approaches or Treatments 
What other choices do I have if I do not take part in this study?  
This is not a treatment trial.  Instead of being in this study, you have the following options: 
• Not participating in this study or 
• Taking part in another study 
Risks or Discomforts of Participation 
Risks of 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 
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.  
 
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 
 
 


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:   13-C-0145 
CONTINUATION: page 4 of 9 pages 
 
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 Eovist 
Eovist has been generally safe when given to people for its FDA approved for imaging of liver 
disease. Side effects of Eovist may occur in this trial.  If they do happen it is usually right around 
the time that Eovist 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) 
• feeling hot, nausea, headache 
Risks from Biopsy 
Biopsies are normally performed under the guidance of an imaging technique. Each procedure 
requires a separate consent prior to the biopsy. The risks may include:  
• Pain and discomfort. The amount of pain and discomfort will vary, depending on the 
location of the biopsy site. These risks can be discussed with the study doctor.  
• Minor bleeding at the biopsy site.  
• Tenderness at the biopsy site.  
• Scarring at the biopsy site.  
• Rarely, an infection at the biopsy site.  
Uncommonly, complications from biopsies can be life threatening. As with any interventional 
procedure, other potentially serious complications from bleeding or organ damage may occur. 
These might require additional surgical intervention. 
Radiation Exposure: 
This research study involves exposure to radiation from CT guided biopsy (the effective dose 
from one CT guided biopsy is 0.15rem). This radiation exposure is not required for your medical 
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 
 
 


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:   13-C-0145 
CONTINUATION: page 5 of 9 pages 
 
care and is for research purposes only. The amount of radiation you will receive in this study is 
below the guideline of 5 rem (or 0.5 rem in children) per year allowed for research subjects by 
the NIH Radiation Safety Committee. The average person in the United States receives a 
radiation exposure of 0.3 rem per year from natural sources, such as the sun, outer space, and the 
earth's air and soil. If you would like more information about radiation, please ask the 
investigator for a copy of the pamphlet, An Introduction to Radiation for NIH Research Subjects.  
While there is no direct evidence that the amount of exposure received from participating in this 
study is harmful, there is indirect evidence it may not be completely safe. There may be a very 
slight increase in the risk of cancer.  
Please tell your doctor if you have had any radiation exposure in the past year, either from other 
research studies or from medical tests or care, so we can make sure that you will not receive too 
much radiation. Radiation exposure includes x-rays taken in radiology departments, cardiac 
catheterization, and fluoroscopy as well as nuclear medicine scans in which radioactive materials 
were injected into your body. 
Potential Benefits of Participation 
Are there benefits to taking part in this study?  
There is no direct benefit to participating in this study. However, the knowledge gained from this 
study may help others in the future. 
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. 
 
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 
 
 


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:   13-C-0145 
CONTINUATION: page 6 of 9 pages 
 
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 
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. 
Stopping Participation in the study 
Your doctor may decide to stop your participation for the following reasons: 
• if he/she believes that it is in your best interest 
• if you have side effects from the procedures that your doctor thinks are too severe 
 
In this case, you will be informed of the reason therapy 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. If you withdraw your consent and leave the trial, 
any samples of yours that have been obtained for the study and stored at the NCI can be 
destroyed upon request. However, any samples and data generated from the samples that have 
already been distributed to other researchers or placed in the research databases cannot be 
recalled and destroyed. 
 
Conflict of Interest 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  The following link contains details on this process 
http://ethics.od.nih.gov/procedures/COI-Protocol-Review-Guide.pdf.  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.  
 
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 
 
 


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:   13-C-0145 
CONTINUATION: page 7 of 9 pages 
 
Optional Studies 
We would like to keep some of the specimens and data that are collected for future research.  
These specimens and data will be identified by a number and not your name.  The use of your 
specimens and data will be for research purposes only and will not benefit you.  It is also 
possible that the stored specimens and data may never be used. Results of research done on your 
specimens and data will not be available to you or your doctor. It might help people who have 
cancer and other diseases in the future.   
If you decide now that your specimens and data can be kept for research, you can change your 
mind at any time. Just contact us and let us know that you do not want us to use your specimens 
and/or data.  Then any specimens that remain will be destroyed and your data will not be used 
for future research.  
Please read each sentence below and think about your choice. After reading each sentence, circle 
and initial the answer that is right for you. No matter what you decide to do, it will not affect 
your care. 
1. My specimens and data may be kept for use in research to learn about, prevent, or treat cancer 
or other health problems.  
 
Yes              No               Initials_________ 
 
2. Someone may contact me in the future to ask permission to use my specimens and/or data in 
new research not included in this consent.  
 
Yes              No               Initials_________ 
 
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 
 
 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:  13-C-0145 
CONTINUATION: page 8 of 9 pages 
 
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, Ismail Baris Turkbey, M.D., Building 10, Room B3B85, Telephone:  301-
443-2315. You may also call the Clinical Center Patient Representative at 301-496-2626. If you 
have any questions about the use of your specimens or data for future research studies, you may 
also contact the Office of the Clinical Director, Telephone:  301-496-4251.  
5. 
Consent Document.  Please keep a copy of this document in case you want to read it 
again. 
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 
 
 
 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:  13-C-0145 
CONTINUATION: page 9 of 9 pages 
 
 
 
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 
 
 
 
Print Name 
Signature of Parent(s)/Guardian 
Date 
 
 
 
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 12, 2015 THROUGH JANUARY 11, 2016.  
 
 
 
 
  
 
 
  
 
Signature of Investigator 
Date 
 
 
 
Print Name 
Signature of Witness 
Date 
 
 
 
Print Name 
 
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