18F-DCFPyL PET/CT in Hepatocellular Carcinoma
Phase: PHASE2
Conditions: Hepatocellular Carcinoma
Sponsor: National Cancer Institute (NCI)

Abbreviated Title: 18F-DCFPyL in HCC
Version Date: 12/01/2023
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Abbreviated Title: 18F-DCFPyL in HCC
NIH Protocol #: 000080
Version Date: 12/01/2023
NCT: NCT05009979
Title: 18F-DCFPyL PET/CT in Hepatocellular Carcinoma
NIH Principal Investigator:
Freddy E. Escorcia, MD, PhD
Molecular Imaging Branch
National Cancer Institute
Building 10, Rm 1B55
9000 Rockville Pike
Bethesda, MD 20892
Phone: 240-858-3062
E-mail: freddy.escorcia@nih.gov
Drug Name:
18F-DCFPyL
18F-FDG
IND Number:
133631
133631
Sponsor:
NCI CCR
NCI CCR
Manufacturer:
PET department, NIH
Commercial
Coordinating Center: NCI, CCR

Abbreviated Title: 18F-DCFPyL in HCC
Version Date: 12/01/2023
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PRÉCIS 
Background:

Prostate specific membrane antigen is overexpressed in high-grade tumors, and increases 
when de-differentiation, metastatic or hormone-refractory disease occur, making the 
expression level a prognostic factor for disease outcome. 

It has been shown that PSMA can be expressed not only on prostate cancer cells, but also 
on cell lines of other malignancies, as well as tumor endothelium.

A recent publication reported that nearly 95% of hepatocellular carcinoma (HCC) stained 
positive for PSMA in the tumor vasculature. Research suggests that the process of 
endothelial cell recruitment to HCC occurs early and throughout the process of hepatic 
tumorigenesis, making an endothelial cell tracer an ideal marker to detect early disease.

18F-DCFPyL, a second generation PSMA PET agent, binds with high affinity to PSMA 
yet clears rapidly from the blood pool and thus, whole-body PET imaging with this agent, 
may provide a new tool in staging high risk cancers and detecting recurrent disease.

We propose to expand our clinical work using 18F-DCFPyL, and evaluate its usefulness 
for detecting sites of hepatocellular carcinoma. 
Objective:

To assess the ability of 18F-DCFPyL PET/CT imaging to detect sites of hepatocellular 
carcinoma
Eligibility:

Participants  18 years old 

High radiological suspicion of hepatocellular carcinoma (HCC) with at least one 
measurable lesion on standard imaging modality (CT and/or MRI) 

Eastern Cooperative Oncology Group (ECOG) Performance score of 0 to 2
Design:

This is a multi-site imaging study enrolling participants with suspected hepatocellular 
carcinoma. The accrual ceiling is set to 50 participants.

All participants will undergo a baseline 18F-DCFPyL PET/CT scan. A standard of care 
CT and/or MRI will be performed within 2 months of the 18F-DCFPyL PET/CT. 
Participants will be also scanned with an 18F-FDG PET/CT imaging within 
approximately 2 weeks of the 18F-DCFPyL PET/CT imaging. 

Participants will be scheduled to undergo a biopsy prior to or during standard of care 
local treatment for HCC (e.g., resection, radiofrequency ablation, microwave ablation, 
transarterial embolization (TAE), stereotactic body radiotherapy (SBRT)). 

Participants with a baseline positive 18F-DCFPyL-PET/CT imaging (i.e. with the 
presence of DCFPyL-avid tumor/s) and biopsy confirming HCC diagnosis will undergo a 
post-treatment 18F-DCFPyL PET/CT imaging during the first routine follow-up period, 
typically within 16 weeks. Subjects with negative tumor uptake at baseline 18F-DCFPyL-
PET/CT will not be re-scanned post-treatment but will remain in follow-up. 

Participants with a positive HCC biopsy will be followed for 5 years to assess 
progression free survival.

Abbreviated Title: 18F-DCFPyL in HCC
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TABLE OF CONTENTS 
PRÉCIS............................................................................................................................................2
TABLE OF CONTENTS ................................................................................................................3
STATEMENT OF COMPLIANCE ................................................................................................7
1
INTRODUCTION ...................................................................................................................8
1.1
Study Objectives ...............................................................................................................8
1.1.1
Primary Objective......................................................................................................8
1.1.2
Secondary Objectives ................................................................................................8
1.1.3
Exploratory Objectives ..............................................................................................8
1.2
Background and Rationale................................................................................................8
1.2.1
18F-DCFPyL...............................................................................................................8
1.2.2
Toxicity and Pharmacology.....................................................................................10
1.2.3
Safety .......................................................................................................................11
1.3
Study Rationale...............................................................................................................11
1.3.1
PSMA Expression in Human Cancers.....................................................................11
1.3.2
Hepatocellular Carcinoma (HCC) ...........................................................................12
1.3.3
Hepatocellular Carcinoma and PSMA.....................................................................12
1.3.4
18F-DCFPyL in HCC ...............................................................................................14
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT .......................................................14
2.1
Eligibility Criteria ...........................................................................................................14
2.1.1
Inclusion Criteria .....................................................................................................14
2.1.2
Exclusion Criteria ....................................................................................................15
2.2
Recruitment Strategies ....................................................................................................15
2.3
Screening Evaluation ......................................................................................................15
2.3.1
Screening activities performed prior to obtaining informed consent ......................15
2.3.2
Screening activities performed after a consent for screening has been signed........15
2.4
Screen Failures................................................................................................................16
2.5
Intervention Assignment Procedures ..............................................................................16
3
STUDY IMPLEMENTATION .............................................................................................17
3.1
Study Design...................................................................................................................17
3.2
Agent Administration......................................................................................................17
3.2.1
18F-DCFPyL administration.....................................................................................17

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3.2.2
18F-DCFPyL PET/CT imaging ................................................................................18
3.2.3
18F-FDG PET/CT imaging.......................................................................................18
3.3
Study Calendar................................................................................................................19
3.4
Surgical Guidelines.........................................................................................................22
3.5
Cost and Compensation ..................................................................................................22
3.5.1
Costs ........................................................................................................................22
3.5.2
Compensation ..........................................................................................................22
3.6
Criteria for Removal from Protocol intervention and Off Study Criteria.......................22
3.6.1
Criteria for removal from protocol intervention......................................................22
3.6.2
Off-Study Criteria....................................................................................................23
3.6.3
Lost to Follow-up ....................................................................................................23
4
CONCOMITANT MEDICATIONS/MEASURES...............................................................23
5
CORRELATIVE STUDIES FOR RESEARCH ...................................................................24
5.1
Biospecimen Collection ..................................................................................................24
5.2
Correlative Analyses.......................................................................................................27
5.2.1
IHC and PSMA Staining on Tissue Samples ..........................................................27
5.2.2
HCC Blood Biomarker Studies/Tumor Marker Tests .............................................27
5.2.3
Analysis of Extracellular Vesicles and Particles (EVPs) ........................................27
5.2.4
Next Generation Sequencing from Tissue and Blood Samples...............................27
5.3
Instructions for participating sites to ship tumor samples...............................................28
5.4
Sample Storage, Tracking and Disposition.....................................................................28
5.5
Samples for Genetic/Genomic Analysis .........................................................................28
5.5.1
Description of the scope of genetic/genomic analysis.............................................28
5.5.2
Description of how privacy and confidentiality of medical information/biological 
specimens will be maximized................................................................................................28
5.5.3
Management of Results ...........................................................................................28
5.5.4
Genetic Counseling..................................................................................................29
6
DATA COLLECTION AND EVALUATION .....................................................................29
6.1
Data Collection ...............................................................................................................29
6.2
Data Sharing Plans..........................................................................................................30
6.2.1
Human Data Sharing Plan .......................................................................................30
6.2.2
Genomic Data Sharing Plan.....................................................................................30

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6.3
Toxicity Criteria..............................................................................................................30
7
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN...31
7.1
Definitions.......................................................................................................................31
7.2
OHSRP Office of Compliance and Training / IRB Reporting........................................31
7.2.1
Expedited Reporting ................................................................................................31
7.2.2
IRB Requirements for PI Reporting at Continuing Review ....................................31
7.3
NCI Guidance for Reporting Expedited Adverse Events for Multi-Center Trials .........31
7.4
NIH Required Data and Safety Monitoring Plan............................................................32
7.4.1
Principal Investigator/Research Team.....................................................................32
8
SPONSOR PROTOCOL/SAFETY REPORTING................................................................32
8.1
Definitions.......................................................................................................................32
8.1.1
Adverse Event..........................................................................................................32
8.1.2
Serious Adverse Event (SAE) .................................................................................32
8.1.3
Life-threatening .......................................................................................................33
8.1.4
Severity....................................................................................................................33
8.1.5
Relationship to Study Product .................................................................................33
8.2
Assessment of Safety Events ..........................................................................................33
8.3
Reporting of Serious Adverse Events .............................................................................34
8.4
Waiver of expedited reporting to CCR ...........................................................................34
8.5
Reporting Pregnancy.......................................................................................................34
8.5.1
Maternal Exposure .................................................................................................34
8.5.2
Paternal Exposure ....................................................................................................34
8.6
Regulatory Reporting For Studies Conducted Under CCR Sponsored Ind....................35
8.7
Sponsor Protocol Deviation Reporting ...........................................................................35
9
CLINICAL MONITORING PLAN ......................................................................................35
10
STATISTICAL CONSIDERATIONS ..................................................................................36
10.1
Primary Endpoint ........................................................................................................36
10.2
Secondary Endpoints...................................................................................................36
10.3
Exploratory Endpoints.................................................................................................37
10.4
Sample Size Determination.........................................................................................37
10.5
Analysis of the Primary Endpoint ...............................................................................37
10.6
Analysis of the Secondary Endpoints..........................................................................37

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10.7
Analysis of Exploratory endpoints..............................................................................37
10.8
Interim Futility Analysis and Early Stopping Rule.....................................................38
11
COLLABORATIVE AGREEMENTS..................................................................................38
11.1
Transfers associated with correlative studies conducted under an approved protocol38
11.2
Multi-Institutional Guidelines .....................................................................................38
11.2.1
IRB Approvals.........................................................................................................38
12
HUMAN SUBJECTS PROTECTIONS................................................................................39
12.1
Rationale For Subject Selection ..................................................................................39
12.2
Participation of Children .............................................................................................39
12.3
Evaluation of Benefits and Risks/Discomforts ...........................................................39
12.3.1
Risk/Benefit Assessment .........................................................................................39
12.4
Consent Process and Documentation ..........................................................................40
13
REGULATORY AND OPERATIONAL CONSIDERATIONS..........................................41
13.1
Study Discontinuation and Closure.............................................................................41
13.2
Quality Assurance and Quality Control ......................................................................41
13.3
Conflict of Interest Policy ...........................................................................................42
13.4
Confidentiality and Privacy.........................................................................................42
14
PHARMACEUTICAL INFORMATION/COMMERCIAL IMAGING ..............................43
14.1
18F-DCFPyL (IND: 133631) .......................................................................................43
14.1.1
Source/Acquisition and Accountability...................................................................43
14.1.2
Toxicity....................................................................................................................43
14.1.3
Formulation and Preparation ...................................................................................43
14.1.4
Stability and Storage................................................................................................44
14.1.5
Administration Procedures ......................................................................................44
14.2
18F-FDG (IND: 133631)..............................................................................................44
14.2.1
Source/Acquisition and Accountability...................................................................44
14.2.2
Administration Procedures ......................................................................................44
15
REFERENCES ......................................................................................................................45
16
APPENDICES .......................................................................................................................48
16.1
Appendix A - Performance Status Criteria..................................................................48

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STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Council on Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval. Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled. Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study. In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.

Abbreviated Title: 18F-DCFPyL in HCC
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1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary Objective

To assess the ability of 18F-DCFPyL PET/CT imaging to detect sites of hepatocellular 
carcinoma (HCC).
1.1.2
Secondary Objectives

Compare the ability of 18F-DCFPyL PET/CT to detect HCC with standard of care imaging 
(CT and/or MRI), and 18F-FDG PET/CT.

To assess the ability of 18F-DCFPyL PET/CT imaging to assess treatment response to local 
therapy.
1.1.3
Exploratory Objectives

Compare the distribution of 18F-DCFPyL uptake with standard of care CT and/or MRI.

Compare focal abnormal 18F-DCFPyL uptake with focal abnormalities identified on 18F-FDG 
PET/CT.

Compare PSMA expression with 18F-DCFPyL uptake. 

Compare tumor viability and metabolism determined by 18F-FDG PET imaging with 18F-
DCFPyL uptake.

Evaluate 18F-DCFPyL uptake with 5 year overall survival and 5 year progression free 
survival.

Evaluate tumor biomarkers in blood, urine and tissue samples.
1.2
BACKGROUND AND RATIONALE
1.2.1
18F-DCFPyL
Dr. Pomper’s group at Johns Hopkins University developed a second-generation low molecular 
weight, PSMA targeted radiotracer, 2-(3-(1-carboxy-5-[(6-[18F] fluoro-pyridine-3-carbonyl)-
amino]-pentyl)-ureido)-pentanedioic acid (18F-DCFPyL). This compound is similar to the first-
generation molecule but with enhanced characteristics. They found tissue binding affinity to be 
more than 5 times greater than 18F-DCFBC and with significantly less blood pool activity. Their 
preclinical studies in prostate cancer mice models revealed a maximum target to muscle 
background ratio of 400:1 at 120 minutes compared to 18F-DCFBC’s ratio of 20:1 [1]. They 
noted comparably favorable pharmacokinetics and dosimetry profile.
In their first-in-human study [2], nine prostate cancer participants were evaluated with this tracer 
to assess safety, biodistribution and radiation dosimetry with favorable results. Physiologic 
radiotracer activity is seen in the salivary glands, lacrimal glands, liver, spleen and intestines 
with excretion through the kidneys and bladder. Blood pool activity rapidly cleared. The 
effective dose for a 370 MBq (8 mCi) dose of 18F-DCFPyL was 6.1 mGy (0.61 rem) or 0.0165 
mSv/MBq. The highest radiation dose is the kidneys (0.0945 mGy/MBq) then the bladder wall 

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(0.0864 mGy/MBq) which can be ameliorated by continuous bladder irrigation, submandibular 
glands (0.0387 mGy/MBq) and liver (0.0380 mGy/MBq). Radiation dose estimates for the other 
organs are in Table 1. More recently, several publications from the Johns Hopkins group have 
studied the viability of using 18F-DCFPyL in prostate cancer staging [3], biochemical recurrence 
[4] and metastatic disease [5, 6]. 
Table 1. Radiation dose estimates for 18F-DCFPyL
   
Tumor uptake was much higher with 18F-DCFPyL than 18F-DCFBC and increased with time. 
Focal radiotracer activity could be seen in some lesions at the earliest imaging point at 5 minutes 
and all known lesions were visualized with highest uptake after 2 hours post-injection. 18F-
DCFPyL uptake identified cancer lesions in the bone, prostate, lymph nodes and soft tissue. 
They did note that most lesions were visualized by 1 hour post-injection; however, there were a 
few small lesions only visible at 2 hours. They suggested that participants with biochemical 
recurrence might be best imaged at the 2 hour point (Figure 1). 

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Figure 1. 18F-DCFPyL PET images of a prostate cancer participant with multiple bone and 
lymph node disease. 
1.2.2
Toxicity and Pharmacology
1.2.2.1
Toxicity in Animals
A toxicity report “14-Day Study to Determine Toxicity of 18F-DCFPyL from a Single 
Intravenous (IV) Dose in Sprague Dawley Rats”, SoBran Study Number: SB-MP-001, was 
performed by SoBran Inc. The following summary is taken from that report. 
The purpose of this study was to evaluate the toxicity of 18F-DCFPyL following a single 
intravenous dose in rats. This study consisted of two test article treatment groups of ten male and 
female Sprague-Dawley rats per group dosed with DCFPyL at 0.1 and 0.5 mg/kg. An additional 
group of ten males and ten females received the vehicle, 5% Dextrose, and served as the control. 
All rats received a dose volume of 5 mL/kg. The rats were dosed intravenously once on Study 
Day 1. Five male and five female rats from each group were bled on Study Day 3 and the 
remaining rats were bled on Study Day 15. All animals were euthanized and necropsied 
following blood collection. Parameters evaluated for test article effect included survival, clinical 
observations, body weight, body weight gain, clinical pathology, gross pathology, organ weights, 
and microscopic pathology.
All rats survived to the scheduled termination and remained bright, alert and responsive during 
the study. No abnormal findings were indicated during cage-side or hands-on observations. One 
female rat treated with the vehicle control and one female rat treated with 0.1 mg/kg DCFPyL 
lost weight between Days 8 and 15. All rats treated with 5% Dextrose or DCFPyL gained weight 
during the course of the study. 
There were no treatment related changes seen in the hematology, coagulation, or clinical 
chemistry data. Organ weights showed some variance but microscopic findings in the Day 3 and 
Day 15 rats were considered incidental and not directly related to the test article. 
Under the conditions of this study, there were no treatment related findings in Sprague Dawley 
rats three or fifteen days after a single intravenous dose of 18F-DCFPyL at 0.1 mg/kg and 0.5 
mg/kg.

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Thus, similar toxicity was observed for the second-generation compound DCFPyL and was 
awarded a physician sponsored FDA exploratory IND based on this acceptable pre-clinical data 
(IND#121,064) for 18F-DCFPyL as a PET radiopharmaceutical, which is held by Dr. Martin 
Pomper. 
18F-DCFPyL is currently approved by the FDA as a radioactive diagnostic agent indicated for 
positron emission tomography (PET) of prostate-specific membrane antigen (PSMA) positive 
lesions in men with prostate cancer: with suspected metastasis who are candidates for initial 
definitive therapy or with suspected recurrence based on elevated serum prostate specific 
antigen (PSA) level.
1.2.2.2
Toxicity in Humans
Szabo et al [7] first reported the use of 18F-DCFPyL in five participants with metastatic prostate 
cancer and none experienced any severe adverse events. In recent trials at NCI using 18F-
DCFPyL, Mena et al. [8] and Gaur et al. [9] reported no adverse events in prospective studies 
including 90 participants with biochemical recurrence prostate cancer, and 26 participants with 
localized prostate cancer, respectively. Another group has proved 18F-DCFPyL to be safe in a 
larger population of 130 subjects with biochemical recurrence prostate cancer [10]. Three grade I 
NCI CTCAE adverse events were reported. One participant reported a mild headache and 
nosebleed (two adverse events) that resolved without treatment and were deemed unlikely to be 
attributed to the radiotracer. The third event was a decreased platelet count found on routine 
post-imaging follow-up labs that was attributed to the participant starting treatment for prostate 
cancer. No heart rate or blood pressure events occurred that were related to the radiotracer. 
1.2.3
Safety 
The effective radiation dose to participants with 18F-DCFPyL was reported as 0.0165 mSv/MBq 
by Szabo et al [7]. Doses to most radiosensitive organs were much lower than with the first-
generation, 18F-DCFBC. They compared dosing to other similar agents, such as 68Ga 
DOTATATE, which is two times higher in effective radiation dose and 124I MIP, which is at 
least one order of magnitude higher in all measured organs, including radiosensitive organs and 
the whole body. 
1.3
STUDY RATIONALE
1.3.1
PSMA Expression in Human Cancers
Prostate specific membrane antigen (PSMA) has been extensively studied in prostate cancers. 
PSMA is overexpressed in high-grade tumors, and increases when de-differentiation, metastatic 
or hormone-refractory disease occur, making PSMA a prognostic factor for disease outcome [11-
13]. However, PSMA is not entirely prostate-specific and it is expressed in several other 
neoplasms, as well as tumor-associated vasculature [14, 15]. Importantly, PSMA-expression of 
normal endothelium is not observed. 
Several PET radiotracers, including small-molecule inhibitors (known as ligands) targeting 
PSMA receptor have been developed, such as DCFPyL to facilitate the diagnosis of prostate 
cancer in humans [2, 5, 16]. 

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1.3.2
Hepatocellular Carcinoma (HCC)
Hepatocellular carcinoma (HCC) accounts for about 80% of all primary liver cancer. It is the 
fifth most common cancer world-wide and the third most common cause of cancer-related 
mortality [17]. Current guidelines of the American Association for the Study of Liver Disease 
and the European Association for the Study of the Liver recommend HCC surveillance with 
abdominal ultrasound every 6 months in participants at high risk of developing the disease. 
Participants diagnosed in early stages of HCC are eligible for potentially curative therapy. 
Therefore, early diagnosis and accurate staging are critical for a favorable prognosis. Curative-
intent therapies for HCC include surgical resection, liver transplantation, microwave or 
radiofrequency ablation in case of small tumors [18]. 
Imaging of HCC at diagnosis is challenging, and assessment of HCC recurrence after treatment 
is also difficult because it can be confounded by coagulative necrosis, hematomas, abscesses, and 
fluid or bile collections [19]. Standard of care imaging modalities used in participants with HCC 
are ultrasound (with or without contrast) and multiphasic CT or MRI. Each method has its 
shortcomings, the major one being the lack of correlation between radiologic appearance and 
biologic activity. The imaging of liver lesions in cirrhotic participants is complex and 
challenging. The cirrhotic liver acquires a nodular architecture with altered vascularity, making 
difficult the differentiation of regenerative nodules from early HCC and metastases from other 
primary tumors. The challenge is even greater in participants who undergo ablative therapies for 
known HCC lesions.
Hence, there is a need for an imaging modality that can be used to localize HCC tumors more 
accurately. Functional imaging with PET has so far not played a major role in the diagnosis or 
surveillance of HCC, and the most commonly used PET tracer, FDG, is not routinely used since 
only a minority of FDG is taken up by HCC tumors [20], with suboptimal sensitivity (<50%) for 
detection of HCC tumors, being inferior to CT [21]. 
1.3.3
Hepatocellular Carcinoma and PSMA
It has been shown that PSMA can be expressed not only on prostate cancer cells, but also on cell 
lines of other malignancies, as well as tumor endothelium. A recent publication reported that 
nearly 95% of hepatocellular cancers stained positive for PSMA in the tumor vasculature. Zhu et 
al. [22] suggested that the process of endothelial cell recruitment to HCC occurs early and 
throughout the process of hepatic tumorigenesis, making an endothelial cell tracer an ideal 
marker to detect early disease. In a recent study assessing 100 HCC tissue samples using 
immunohistochemical staining, Jiao and collaborators [23] reported PSMA expression in more 
than 50% of tumor-associated vasculature in 26% of tissues, and PSMA expression in less than 
50% of vasculature in 48% of tissues. Furthermore, high vascular PSMA expression was also 
associated with poor prognosis in participants with HCC, and could be used as an independent 
prognostic marker for HCC [23]. Tolkach et al. [24] found that the majority of hepatocellular 
carcinomas (89.9%) show high levels of PSMA expression on tumor neovasculature and on 
canalicular membrane of the tumor cells (4.1% of tumors) [24]. To date, most of the reported 
findings with PSMA-targeted PET radiotracers in HCC have been in few case reports [25] and 
small case series [26]. Recently, 68Ga-PSMA PET imaging showed encouraging preliminary 
results for imaging HCC in a small cohort of 7 participants. 68Ga-PSMA PET-CT showed 
superiority over 18F-FDG PET-CT in imaging participants with HCC. All but a single tumor 
lesion were associated with 68Ga-PSMA uptake higher than that of the surrounding liver 

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parenchyma (Figure 2 and Figure 3), with a mean uptake 3.6 times higher than that of the 
background liver. The increased 68Ga-PSMA uptake in HCC was corroborated by the results of 
immunohistochemistry analysis showing PSMA staining of the endothelial cells lining of vessels 
that are penetrated by tumor. Furthermore, 68Ga-PSMA PET appeared to differentiate necrotic 
from viable tumor (Figure 3), which could dramatically improve detection of HCC recurrence 
following local ablative therapies [26]. In another recent study, Kuyumcu et al. [27] was able to 
visualize advanced HCC using 68Ga-PSMA-PET/CT in 16 out of 19 cases with high tumor-to-
background ratio. Interestingly, 68Ga-PSMA standard uptake value (SUVmax) correlated with 
participant overall survival [27].
Few direct comparisons between 18F-DCFPyL and 68Ga-PSMA-PET have been reported in 
prostate cancer population and only in one manuscript. Dietlein et al. [28] reported comparable 
biodistributions for both tracers, but slightly higher sensitivity for 18F-DCFPyL compared to 
68Ga-PSMA-11 (88% vs 66%) in participants with biochemical recurrence of prostate cancer. 
Figure 2. Enhancing HCC. Increased uptake of 68Ga-PSMA was seen within the tumor at the 
left liver lobe (arrows) as well as in tumor thrombus in the left portal vein (arrowheads). These 
lesions showed no significant FDG avidity. 
Figure 3. HCC lesions with mosaic contrast enhancement on CT angiography. Increased 68Ga-
PSMA uptake was identified only in the enhancing area (arrows). Lesions were non-FDG-avid. 

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1.3.4
18F-DCFPyL in HCC
We propose to expand clinical work using 18F-DCFPyL PET imaging in prostate cancer 
participants, and evaluate its usefulness in detecting sites of hepatocellular carcinoma. 18F-
DCFPyL distribution and tumor uptake will be compared with the results of CT, and /or MRI. 
This may provide data to support a future trial using 18F-DCFPyl PET/CT, define its role in the 
diagnosis and surveillance of HCC, especially following treatment. This study should offer 
insights into how and when 18F-DCFPyL could be used in the clinical setting to direct proper 
management. 
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria
2.1.1.1
High radiological suspicion of hepatocellular carcinoma (LR4 or LR5 based on the most 
current version of LI-RADS) with at least one measurable lesion on standard imaging 
modality (CT and/or MRI). 
2.1.1.2
Eligible for local therapies (included but not limited to surgical resection, stereotactic 
radiation therapy, transarterial chem/radio/bland embolization, microwave ablation, 
radiofrequency ablation).
2.1.1.3
Ability to take oral medication and be willing to adhere to the study intervention 
regimen.
2.1.1.4
Age >18 years. 
2.1.1.5
ECOG performance status <2 (see Appendix A). 
2.1.1.6
Known human immunodeficiency virus (HIV)-infected individuals must be on effective 
anti-retroviral therapy with undetectable viral load within 6 months.
2.1.1.7
Known chronic hepatitis B virus (HBV) infected individuals, must be on suppressive 
therapy with undetectable viral load.
2.1.1.8
Individuals with a history of hepatitis C virus (HCV) infection must have been treated 
and cured. 
2.1.1.9
The effects of 18F-DCFPyL (study drug) on the developing human fetus are unknown. 
For this reason and because this agent as well as other therapeutic agents used in this 
trial are known to be teratogenic, women of child-bearing potential and men must agree 
to use adequate contraception (hormonal or barrier method of birth control; abstinence) 
prior to study entry and for 2 months after each study PET/CT imaging. Should a 
woman become pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she should inform her treating physician immediately.
2.1.1.10 Ability of subject to understand and the willingness to sign a written informed consent 
document.

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2.1.2
Exclusion Criteria
2.1.2.1
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to 18F-DCFPyL or other agents used in study.
2.1.2.2
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements.
2.1.2.3
Subjects with severe claustrophobia unresponsive to oral anxiolytics.
2.1.2.4
Other medical conditions deemed by the principal investigator (or associates) to make 
the subject unsafe/ineligible for protocol procedures.
2.1.2.5
Subjects weighing > 350 lbs (weight limit for scanner table), or unable to fit within the 
imaging gantry.
2.1.2.6
Serum creatinine > 2 times the upper limit of normal.
2.1.2.7
Pregnant women are excluded from this study because 18F-DCFPyL is an agent with the 
potential for teratogenic or abortifacient effects. as well as other agents used in this trial 
are known to be teratogenic.
2.2
RECRUITMENT STRATEGIES
This protocol may be abstracted into a plain language announcement posted on NIH websites 
and on NIH social media platforms. Participants will also be identified via internal referrals from 
each participating site institution, and outside referrals. 
2.3
SCREENING EVALUATION
2.3.1
Screening activities performed prior to obtaining informed consent
Minimal risk activities that may be performed before the subject has signed a consent include the 
following: 

Email, written, in person or telephone communications with prospective subjects 

Review of existing medical records to include H&P, laboratory studies, etc. 

Review of existing MRI, x-ray, or CT images

Review of existing photographs or videos

Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes
2.3.2
Screening activities performed after a consent for screening has been signed
The following activities will be performed only after the subject has signed the study consent OR 
the consent for study 01-C-0129 (for NIH only provided the procedure is permitted on that 
study) on which screening activities may also be performed. Assessments performed at outside 
facilities or on another NIH protocol within the timeframes below may also be used to determine 
eligibility once a participant has signed the consent.

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Within 30 days prior to administration of 18F-DCFPyL, unless otherwise specified:

CT and/or MRI (outside imaging studies can be used; however, the images must be made 
available in DICOM format for review by MIB staff) (within 2 months prior to 
administration of 18F-DCFPyL).

Medical history, concomitant medication review and physical examination (including 
height, weight, vital signs, and ECOG performance status).

Hematological profile: CBC with differential and platelet count 

Acute care profile: sodium, potassium, chloride, total CO2, creatinine, glucose, urea 
nitrogen, eGFR 

Serum or urine pregnancy test for female participants of childbearing age (in the absence 
of prior hysterectomy).
2.4
SCREEN FAILURES
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE).
Individuals who do not meet the criteria for participation in this trial (screen failure) because 
prior biopsy did not confirm HCC may be rescreened.
2.5
INTERVENTION ASSIGNMENT PROCEDURES
Cohorts
Number
Name
Description
1
HCC
Participant with radiographically confirmed hepatocellular 
cancer. 
Arms
Number
Name
Description
1
Baseline and Post-
treatment Imaging
18F-DCFPyL PET/CT imaging, CT and/or MRI and 
standard of care local treatment. 
Arm assignment
Participants in cohort 1 will directly be assigned to arm 1.

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3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN
This is an open-label multi-center study recruiting participants with suspected hepatocellular 
carcinoma (with at least one detectable liver lesion on standard of care CT and/or MRI) who are 
eligible to undergo local treatment for HCC (e.g., surgical resection, radiofrequency ablation, 
microwave ablation, transarterial embolization (TAE), stereotactic body radiotherapy (SBRT)). 
Participants will be consented and enrolled through the NIH Clinical Center. 
All participants will undergo a baseline 18F-DCFPyL PET/CT. Within approximately 2 weeks of 
each 18F-DCFPyL PET/CT scan, participants will also be scanned with a 18F-FDG PET/CT 
imaging. 18F-FDG PET/CT may be performed within two weeks before or after each 18F-
DCFPyL PET/CT scan. Each PET/CT imaging must be approximately a day apart. The order 
obtained for 18F-DCFPyL PET/CT and 18F-FDG PET/CT does not matter. 
A CT and/or MRI will be performed within 2 months of the 18F-DCFPyL PET/CT scan. Clinical 
scans performed in this time frame by local providers are also acceptable.
Participants will undergo a biopsy prior to/concurrent with local therapy (more than one lesion 
may be biopsied during the same procedure). The procedure may be performed at the NIH 
Clinical Center or at the participating site (Washington DC Veteran’s Affairs Medical Center). 
The treatment procedure will be scheduled as clinically indicated and samples will be collected 
prior to therapy (or during surgical resection).
An additional 18F-DCFPyL PET/CT imaging will be performed during the first routine post local 
therapy follow-up for participants with a positive baseline 18F-DCFPyL-PET/CT (i.e. the 
presence of DCFPyL-avid tumor/s) and with a biopsy confirming HCC diagnosis. Subjects with 
negative tumor uptake at the baseline 18F-DCFPyL-PET/CT and with a biopsy confirming HCC, 
will not have study-related imaging post-treatment and will remain in follow-up. Subjects with 
biopsies negative for HCC will be taken off protocol. 
Participants with a positive HCC biopsy will be followed by clinical chart review, phone-call, 
email follow-up or any other NIH approved remote platform for tumor markers and radiologic 
evidence of recurrence over a 5-year period from the last 18F-DCFPyL PET/CT imaging. A set of 
imaging (18F-DCFPyL PET/CT, 18F-FDG PET/CT, CT/MRI) may be performed and research 
samples may be collected at the time of tumor recurrence per PI discretion. Should participants 
undergo another treatment during the follow up period, a biopsy may be done per PI discretion 
(more than one lesion may be biopsied during the same procedure).
For detailed study and schedule of procedures, refer to section 3.3.
3.2
AGENT ADMINISTRATION
3.2.1
18F-DCFPyL administration
The target administered activity will be 9 mCi; dose variations will be in accordance with the 
Nuclear Regulatory Commission (NRC) standard dose variation (i.e. 20%) permitted for 
diagnostic clinical studies. Due to potential unpredictable delays and the short half-life of 18F, the 
total dose of 18F-DCFPyL administered may be reduced at the discretion of the principal 
investigator or their designee. 

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The administration site should be evaluated just before, during and after injection, to assess for 
extravasation and/or for the presence of signs of local irritation.
Because there is an unknown but potential risk for adverse events in nursing infants secondary to 
exposure of the mother to 18F, breastfeeding should be discontinued for 12 hours after 
administration of either 18F-DCFPyL or 18F-FDG.
3.2.2
18F-DCFPyL PET/CT imaging
The 18F-DCFPyL PET/CT imaging will consist of the 18F-DCFPyL injection, followed by a ~45 
min dynamic CT imaging of a single bed position (including the liver lesion), and a static whole-
body PET/CT imaging (top of head to mid-thighs) performed at 1 hour (+/- 10 minutes) post 18F-
DCFPyL injection. Only a single injection of 18F-DCFPyL is required. The initial 45 minutes 
dynamic regional scan will be used to determine the kinetics of 18F-DCFPyL within the tumor as 
compared with normal liver and other background.
Participants will be encouraged to hydrate and urinate frequently after administration of the drug. 
Summary of scanning procedure: 
1. IV placement 
2. Administration of 18F-DCFPyL; begin AE monitoring
3. Dynamic PET/CT imaging of a single field-of-view (including the liver lesion) will be 
performed (~ 45 minutes) 
4. Subject asked to void 
5. 1 hour (+/- 10 minutes) following 18F-DCFPyL injection, a static whole body PET/CT 
imaging will be performed (~30-45 minutes in duration) 
6. Follow-up AE query ~1-3 days post-injection 
3.2.3
18F-FDG PET/CT imaging
The 18F-FDG PET/CT imaging will consist of an 18F-FDG injection and PET/CT imaging 
performed approximately 1 hour post 18F-FDG injection. A corresponding low dose CT scan for 
attenuation correction and co-registration purposes will be performed prior to the PET image. 

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3.3
STUDY CALENDAR
Procedures
Screening1
Baseline 1 
Study Visit 1 
Study Visit 2 10
Follow-up 11
Disease 
Progression
Informed consent
X
Medical Assessment
Demographics
X
Medical history 
X
Concomitant medication review
X
Physical Assessment
ECOG
X
Physical exam (including height and 
weight) 
X
Vital signs
X
 X 2
 X 2
Laboratory Assessment
Hematology (CBC with diff and platelet)
X
X
Serum chemistry/Acute Care Panel 3
X
X
Serum or urine pregnancy test 4
X
X
X
Study Intervention
CT and/or MRI
 X 5
  
 X 5 
 X 12
18F-DCFPyL PET/CT imaging 6
X
X
 X 12
18F-FDG PET/CT imaging 7
X
X
 X 12
Adverse Event Monitoring
Injection site monitoring 8
X 
X
X
Adverse event monitoring/Query 8
X 
X
X

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Procedures
Screening1
Baseline 1 
Study Visit 1 
Study Visit 2 10
Follow-up 11
Disease 
Progression
Correlative studies
Tumor marker tests 9, 13
X
X
X
Exome germline control blood collection
X
Tumor Biopsy 
Concurrent with standard of care therapy (pre-treatment or during surgical 
resection)
Blood and urine for EVP analysis 13
X
X
X
X
Follow-up evaluations
Review of clinical chart, phone call or e-
mail (or any NIH approved platform)
X 
Collection/review of imaging scans
X
1. Performed within 30 days prior to administration of 18F-DCFPyL unless otherwise indicated. Screening procedures such as 
medical assessment may be performed remotely via any NIH approved platforms.
2. Vital signs will be taken prior to injection of 18F-DCFPyL. 
3. Acute care panel: sodium, potassium, chloride, total CO2, creatinine, glucose, urea nitrogen, eGFR 
4. For female participants of childbearing age (in the absence of prior hysterectomy). Pregnancy tests may be performed as clinically 
indicated prior to each scan.
5. CT (Chest/Abdomen/Pelvis) and/or MRI (Abdomen) will be performed within 2 months of each18F-DCFPyL PET/CT. Imaging 
may be performed at certified outside facility and provided to study team.
6. Subjects will undergo 18F-DCFPyL injection and a dynamic PET/CT. Approximately 1 hour (+/- 10 minutes) post 18F-DCFPyL 
injection, a static PET/CT imaging performed. Refer to section 3.2.2 for additional information regarding the scanning procedure. 
7.
18F-FDG PET/CT will be performed within approximately 2 weeks before or after each 18F-DCFPyL scan. Each PET/CT imaging 
must be approximately a day apart. The order obtained for 18F-DCFPyL PET/CT and 18F-FDG PET/CT does not matter.
8. Event monitoring will be done at the time of injection, and 1 hour post injection. All subjects will be contacted by phone at ~1-3 
business days post-injection and will be asked non-leading questions regarding symptoms. At the investigator's discretion, subjects 

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21
with safety concerns noted during the post injection period may remain at the site or be asked to return to the site to undergo 
further safety assessments at the 1-3 business day follow-up time point.
9. Tumor markers include Alpha-fetoprotein, carcinoembryonic antigen, carbohydrate antigen 19.9 (CA19.9) and liver function tests 
(Alkaline Phosphatase, ALT, AST, Total Bilirubin, Direct Bilirubin). Refer to section 5.1 for more details.
10. Only participants with a positive baseline 18F-DCFPyL-PET/CT scan (i.e. with the presence of DCFPyL-avid tumor/s) and a 
biopsy confirming HCC diagnosis will undergo visit 2 for a second 18F-DCFPyL PET/CT (during routine treatment follow up, 
typically within 16 weeks).
11. Follow-up will be performed every 3 months (± 2 weeks) after the last 18F-DCFPyL scan (or after therapy for participants with 
negative baseline 18F-DCFPyL PET/CT and biopsy confirming HCC) for 2 years, and yearly afterwards for an additional 3 years. 
12. If tumor recurrence occurs during the follow-up period, an 18F-DCFPyL PET/CT, 18F-FDG PET/CT, CT/MRI and biopsy may be 
performed any time after recurrence at PI discretion. Biopsy would be performed concurrently with treatment if the latter is 
performed.
13.  Blood collection for tumor markers and EVP analysis may be omitted beyond visit 2 if any issues with scheduling or logistics. 
The same applies to urine collection for EVP analysis.

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3.4
SURGICAL GUIDELINES
Participants may undergo medically indicated surgical procedures for diagnostic and/or 
therapeutic intervention on this protocol as per standard of care for HCC. No surgery will be 
performed solely for the purpose of obtaining research specimens. 
3.5
COST AND COMPENSATION 
3.5.1
Costs
Subjects’ costs will be based on local guidelines as described in the site specific consent. 
3.5.2
Compensation
Participants will be compensated for their participation in the study per NIH HRPP Policy 302 
found at 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. Participants will be 
compensated as follows:
Payment for Visit 
Completion 
Payment for 
Imaging*
($50 per imaging)
Total Possible 
Compensation
Baseline/Study Visit 1
$60 
$100 
$160
Study Visit 2
$60
$150
$210
Disease Progression
$60
$150
$210
*Study related imaging performed at the NIH Clinical Center (CT/MRI, 18F-FDG PET/CT and 
18F-DCFPyL PET/CT)
Compensation will be provided via ACH or debit cards in a prorated manner for each completed 
visits/imaging procedures. Participants that withdraw prior to completion of the study will 
receive compensation for visits/imaging that have been completed until that point. Individual 
participants may decline to receive compensation for participation in research and still participate 
in the study.
3.6
CRITERIA FOR REMOVAL FROM PROTOCOL INTERVENTION AND OFF STUDY CRITERIA
Prior to removal from study, effort must be made to have all subjects complete a safety visit by 
phone approximately ~1-3 business days following the last dose of study intervention.
3.6.1
Criteria for removal from protocol intervention

PI discretion

A serious or intolerable event related to the study agent occurs 

Participant requests to be withdrawn from active intervention

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
18F-DCFPyL is no longer available
3.6.2
Off-Study Criteria

Participants with biopsy that does not confirm HCC diagnosis

Participant requests to be withdrawn from the study 

Participant becomes pregnant

PI discretion

Subject becomes decisionally impaired 

Lost to follow up

Death 

PI decision to close the study

Completion of follow up period

Screen failure
3.6.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she fails to return for 2 scheduled visits 
and is unable to be contacted by the study site staff on at least two (2) separate occasions. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site will attempt to contact the participant and reschedule the missed visit and 
counsel the participant on the importance of maintaining the assigned visit schedule and 
ascertain if the participant wishes to and/or should continue in the study.

Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, an IRB approved certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented in 
the participant’s medical record or study file. 

Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.
4
CONCOMITANT MEDICATIONS/MEASURES
In the event that a subject has a reaction (allergic) to the radiotracer, all appropriate medical 
measures will be taken immediately. In rare instances, this may entail admission to the hospital 
for observation.
Participants are permitted to undergo systemic therapy for their disease during the course of the 
study. However, an attempt should be made to maintain the same systemic therapy during the 
two sets of scans to avoid confounding. 
Participants may also receive standard of care therapy on this study. 

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5
CORRELATIVE STUDIES FOR RESEARCH
5.1
BIOSPECIMEN COLLECTION
Table 2. Summary of Collection of Correlative Samples 
Test/assay
Quantity 
(approx)
Type of tube a
Collection 
timepoint
Location of specimen 
Sample data system 
used
Tissue samples
IHC
PSMA staining
Next Generation Sequencing
4 cores per 
lesion 
(18G)
NA
Concurrently 
with standard 
of care 
treatment
Laboratory of Pathology 
(LP)/COMPASS 
Blood Processing Core (Figg 
lab)
CCR Sequencing Facility
Xin Wang laboratory
Participating sites should 
process and ship samples to 
Figg lab per section 5.3.
Labmatrix
Blood samples
Alpha-fetoprotein b
Carcinoembryonic antigen b
Carbohydrate antigen 19.9 b
3.5 mL
1 SST
Liver function tests (Alkaline 
Phosphatase, ALT, AST, Total 
Bilirubin, Direct Bilirubin) b
3.5 mL
1 Green 
Lithium 
heparin
Within 30 
days of each 
18F-DCFPyL 
PET/CT 
imaging
Participating site Clinical 
Center laboratory 
or 
Outside Clinical facility
C3D

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Test/assay
Quantity 
(approx)
Type of tube a
Collection 
timepoint
Location of specimen 
Sample data system 
used
Germline Mutation Control 
3 mL
1 Sodium 
Citrate tube
Baseline
Laboratory of 
Pathology/COMPASS
Labmatrix
3.5 mL
2 SST tubes
Baseline, 
Study Visit 2 
Follow-up
Progression
Figg lab 
Labmatrix
10 mL
2 Streck DNA 
BCT
Baseline 
Study Visit 2 
Follow-up 
Progression
Figg lab 
Labmatrix
EVP analysis b
20 mL
2 Streck 
complete 
(RNA, EV)
BCT
Baseline 
Study Visit 2 
Follow-up 
Progression
Figg lab
Labmatrix
Urine Sample
EVP analysis b
50mL
Urine cup
Baseline 
Study Visit 2 
Follow-up
Progression
Figg lab 
Labmatrix
a.
Please note that tubes and media may be substituted based on availability with the permission of the PI or laboratory investigator.
b.
May be omitted beyond visit 2 if any issues with scheduling or logistics. 

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5.2
CORRELATIVE ANALYSES
5.2.1
IHC and PSMA Staining on Tissue Samples
Specimen (1 core per lesion) will undergo routine formalin fixation and paraffin embedding, 
immunohistochemistry, tumor diagnosis, and molecular evaluation in the NCI Laboratory of 
Pathology. PSMA staining will also be conducted. The specimen results will be correlated with 
18F-DCFPyL PET/CT and standard CT and/or MRI imaging results.
5.2.2
HCC Blood Biomarker Studies/Tumor Marker Tests 
Alpha-fetoprotein, carcinoembryonic antigen, carbohydrate antigen 19.9 (CA19.9) and liver 
function tests (Alkaline Phosphatase, ALT, AST, Total Bilirubin, Direct Bilirubin) will be 
performed (may done by an outside facility)
5.2.3
Analysis of Extracellular Vesicles and Particles (EVPs)
Blood and urine samples will be used in the Jones Lab (stored in Figg lab) for analysis of 
extracellular vesicles and particles (EVPs). Specifically, we are most interested in measuring the 
concentration and composition of the EVPs that are PSMA+ across the samples, as related to 
PSMA detection on imaging and in response to treatment. We have identified robust methods for 
detecting and isolating PSMA+ EVPs, and then evaluating co-expressed proteins and nucleic 
acids associated with those EVPs. EVPs in general will be processed and evaluated according to 
our published protocols (nano.ccr.cancer.gov), with PSMA+ EVPs enriched by immunoaffinity 
from cell-free blood and urine samples. Our hypothesis is that the molecular cargo and 
composition of the PSMA+ EVPs in liquid biopsies (ie, accessible in blood and urine samples) 
may correlate with 1) imaging extent of PSMA detection, 2) additional histopathologic features 
identified in the targeted biopsies in the study, and 3) the biological / clinical course of PSMA+ 
foci, followed over time, including, but not limited to, local control and time to progression.
The following analysis will be performed:
1. Isolation of EVPs will be performed with size exclusion and affinity chromatography. 
2. Enumeration and characterization of EVPs and their composition will be performed with 
nanoparticle tracking analysis, resistive pulse sensing, and flow cytometry to determine 
whether volume of PSMA+ tissue on imaging correlates with concentration of PSMA+ 
EVPs in blood and/or urine. Routine laboratory assays for protein/DNA/RNA 
quantification will also be performed.
Where sufficient cell free biofluid is available, NGS DNA methylomics will be compared 
between pooled PSMA+ (or other surface marker positive) EVP vs PSMA- (marker negative) vs 
general biofluid isolates to identify distinctive EVP subset cargo signatures that correlate with 
disease extent, progression, or other clinical / histopathologic correlates.
5.2.4
Next Generation Sequencing from Tissue and Blood Samples
In order to address the exploratory goal of characterizing predictive biomarkers of response, 
including but not limited to genomic, transcriptomic (RNA Seq), and/or epigenomic assessments 
of tumor tissue may be performed. Tissue samples will be sent to the Wang laboratory, Figg 
laboratory, Laboratory of Pathology (via Dr. Aldape’s COMPASS program), and CCR 
Sequencing Facility at Frederick National Laboratory for Cancer Research to conduct this 

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analysis. A blood sample will be sent to the Laboratory of Pathology for germline mutation 
control.
5.3
INSTRUCTIONS FOR PARTICIPATING SITES TO SHIP TUMOR SAMPLES
Instructions for collection and shipping of samples will be provided directly to site.
5.4
SAMPLE STORAGE, TRACKING AND DISPOSITION
All specimens obtained in the protocol are used as defined in the protocol. Any specimens that 
are remaining at the completion of the protocol will be stored in the conditions described below. 
The study will remain open so long as sample or data analysis continues. Samples from 
consenting subjects will be stored until they are no longer of scientific value or if a subject 
withdraws consent for their continued use, at which time they will be destroyed. 
If the participant withdraws consent the participants data will be excluded from future 
distributions, but data that have already been distributed for approved research use will not be 
able to be retrieved.
The PI will record any loss or unanticipated destruction of samples as a deviation. Reporting will 
be per the requirements of section 7.2. Participating sites must inform coordinating site PI of any 
loss or unanticipated destruction of samples per section 7.3.
Samples will be barcoded and stored under conditions specified by research laboratory. Sample 
barcodes are linked to participant demographics and limited clinical information. 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 an NIH approved sample storage and 
tracking system. 
5.5
SAMPLES FOR GENETIC/GENOMIC ANALYSIS
5.5.1
Description of the scope of genetic/genomic analysis
Refer to section 5.2.4 of the protocol.
5.5.2
Description of how privacy and confidentiality of medical information/biological 
specimens will be maximized
As stated in section 5.2, unique identifiers are attached to samples and are linked through the secure 
database to medical record information, with the key provided only to researchers on the study. 
Therefore, potential identification would only occur in the event of a data breach – an unlikely 
event given the security standards of the databases utilized. A certificate of confidentiality has 
been obtained (section 13.4). Unlinked genomic data will be deposited in public genomic databases 
such as dbGaP in compliance with the NIH Genomic Data Sharing Policy (6.2.2). The pedigree 
analysis will not be performed.
5.5.3
Management of Results
We plan to contact participants if a clinically actionable gene variant is discovered. Clinically 
actionable findings for the purpose of this study are defined as disorders appearing in the American 
College of Medical Genetics and Genomics recommendations for the return of secondary findings 
that is current at the time of primary analysis. (A list of current guidelines is maintained on the 
CCR intranet: https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists. 

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Unless requested otherwise, participants will be contacted at that time with a request to provide a 
sample to be sent to a CLIA certified laboratory. 
Participants will be requested to maintain up to date contact information to enable future contact
For samples undergoing analysis through the NCI COMPASS, results will be reported per CCR 
SOP ADGC-5, Tumor/Normal Whole Exome Sequencing: Consenting, Ordering, and Obtaining 
Results found at https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.
5.5.4
Genetic Counseling
If the research findings related to causative genes are verified in the CLIA certified lab, the 
participant will be offered the opportunity to schedule a visit, in person (at our expense) or via 
telemedicine on a NIH approved platform to have genetic education and counseling with the 
Genetics Branch, CCR/NCI to explain this result. If the subject does not want to come to NIH or 
participate in a telemedicine visit, a referral to a local genetic healthcare provider will be 
provided (at their expense). This is the only time during the course of the study that incidental 
findings will be returned. No interrogations regarding clinically actionable findings will be made 
after the primary analysis.
6
DATA COLLECTION AND EVALUATION 
6.1
DATA COLLECTION
The PI at each site will be responsible for overseeing entry of data into a 21 CFR Part 11 
compliant data capture system provided by the NCI CCR and ensuring data accuracy, 
consistency, and timeliness. Data quality assurance will be performed per sections 7.4 and 9. 
Data should be received by the coordinating institution at least quarterly. 
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. 
Document AEs from the first study intervention through 3 days after the agent was last 
administered. Beyond the 3 days after the last intervention and through the remaining follow-up, 
only adverse events which are serious need to be recorded.
An abnormal laboratory value will be recorded in the database as an AE only 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 
participant’s outcome. 
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable. 

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Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in section 7.2. 
6.2
DATA SHARING PLANS
6.2.1
Human Data Sharing Plan
What data will be shared?
I will share human data generated in this research for future research as follows:

Coded, linked data in an NIH-funded or approved public repository.

Coded, linked data in BTRIS (automatic for activities in the Clinical Center)

Identified or coded, linked data with approved outside collaborators under appropriate 
agreements.
How and where will the data be shared? 

Data will be shared through:

An NIH-funded or approved public repository. Insert name or names: Clinicaltrials.gov; 
dbGap.

BTRIS (automatic for activities in the Clinical Center)

Approved outside collaborators under appropriate individual agreements.

Publication and/or public presentations.
When will the data be shared? 

Before publication.

At the time of publication or shortly thereafter.
6.2.2
Genomic Data Sharing Plan
This study will comply with the NIH Genomic Data Sharing Policy, which applies to all NIH-
funded research that generates large-scale human or non-human genomic data, as well as the use 
of these data for subsequent research. Large-scale data include genome-wide association studies 
(GWAS), single nucleotide polymorphisms (SNP) arrays, and genome sequence, transcriptomic, 
epigenomic, and gene expression data.
Therefore, unlinked genomic data will be deposited in public genomic databases such as dbGaP 
in compliance with the NIH Genomic Data Sharing Policy. 
6.3
 TOXICITY CRITERIA
The following adverse event management guidelines are intended to ensure the safety of each 
participant while on the study. The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE 
reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 
5.0. A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 

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6.3.1.1
Image Analysis
Target Lesions: Images will be analyzed by MIB staff by identifying, recording and measuring 
measurable target lesions. A segmentation tool will be applied to generate semi-automated 
volume of interests (VOI) within the target lesion(s). Maximum standardized uptake value 
(SUVmax) and tumor volumes will be extracted from the generated target lesion(s) VOIs. 18F-
DCFPyL uptake in major organs and bone marrow will also be measured and mean SUV values 
will be extracted. 
All other lesions (or sites of disease) including any measurable lesions should be identified as 
non-target lesions and should also be recorded. 
Antitumor effect: To determine whether uptake of 18F-DCFPyL correlates with response to 
therapy, target tumor(s) imaging PET parameters, including SUVmax, and tumor volume will be 
compared between responders vs non-responders. Participant response will be based on RECIST 
1.1. criteria and clinical assessment. 
7
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN
7.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.
7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING
7.2.1
Expedited Reporting 
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. Note: Only IND Safety 
Reports that meet the definition of an unanticipated problem will need to be reported per these 
policies.
7.2.2
IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. 
7.3
NCI GUIDANCE FOR REPORTING EXPEDITED ADVERSE EVENTS FOR MULTI-CENTER 
TRIALS
Report events to the Reviewing IRB as per its policy. 
Please also notify the coordinating center PI and study coordinator of your submission at the 
time you make it.
For IND studies, the site PI will also directly submit reports to the CCR as IND sponsor per 
section 8.3.

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7.4
NIH REQUIRED DATA AND SAFETY MONITORING PLAN
7.4.1
Principal Investigator/Research Team 
The clinical research team will meet on a regular basis (weekly) when participants are being 
actively treated on the trial to discuss each participant. 
All data will be collected in a timely manner and reviewed by the principal investigator. Events 
meeting requirements for expedited reporting as described in section 7.2.1 will be submitted 
within the appropriate timelines. 
The principal investigator will review adverse event on each participant 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.
8
SPONSOR PROTOCOL/SAFETY REPORTING
8.1
DEFINITIONS
8.1.1
Adverse Event 
Any untoward medical occurrence in a participant or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product (ICH E6 (R2)).
8.1.2
Serious Adverse Event (SAE)
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 event (see section 8.1.3)

Inpatient hospitalization or prolongation of existing hospitalization 
o
A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration in 
health, is not considered a serious adverse event.
o
A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for participant convenience) is not considered a serious adverse event. 
o
Emergency room visits or stays in observation units that do not result in admission to 
the hospital would not be considered a serious adverse event. The reason for seeking 
medical care should be evaluated for meeting one of the other serious criteria.

Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions

A congenital anomaly/birth defect

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
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 participant or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition.
8.1.3
Life-threatening 
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the participant or subject at immediate 
risk of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. (21CFR312.32).
8.1.4
Severity
The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.
8.1.5
Relationship to Study Product
All AEs will have their relationship to study product assessed using the terms: related or not 
related. 

Related – There is a reasonable possibility that the study product caused the adverse 
event. Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event.

Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event.
8.2
ASSESSMENT OF SAFETY EVENTS
AE information collected will include event description, date of onset, assessment of severity 
and relationship to study product and alternate etiology (if not related to study product), date of 
resolution of the event, seriousness and outcome. The assessment of severity and relationship to 
the study product will be done only by those with the training and authority to make a diagnosis 
and listed on the Form FDA 1572 as the site principal investigator or sub-investigator. AEs 
occurring during the collection and reporting period will be documented appropriately regardless 
of relationship. AEs will be followed through resolution.
SAEs will be:

Assessed for severity and relationship to study product and alternate etiology (if not 
related to study product) by a licensed study physician listed on the Form FDA 1572 as 
the site principal investigator or sub-investigator.

Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database.

Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site principal investigator or sub-investigator.
For timeframe of recording adverse events, please refer to section 6.1. All serious adverse events 
recorded from the time of first investigational product administration must be reported to the 
sponsor with the exception of any listed in section 8.4.

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8.3
REPORTING OF SERIOUS ADVERSE EVENTS
Any AE that meets protocol-defined serious criteria that require expedited reporting must be 
submitted immediately (within 24 hours of awareness) to OSRO Safety using the CCR SAE 
report form. 
All SAE reporting must include the elements described in section 8.2.
SAE reports will be submitted to the Center for Cancer Research (CCR) at: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator. CCR SAE report form and 
instructions can be found at: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions
Following the assessment of the SAE by OSRO, other supporting documentation of the event 
may be requested by the OSRO Safety and should be provided as soon as possible.
8.4
WAIVER OF EXPEDITED REPORTING TO CCR 
Death or hospitalization that is deemed to be due to disease progression, and not attributable to 
the intervention will not be reported as an SAE. The event, and the assessment that it was caused 
by disease progression will be documented in the medical records. The causality assessment of 
Hospitalization will be re‐evaluated any time when new information is received. If the causality 
assessment changes from disease progression to related to the study intervention, SAE report will 
be sent to the Sponsor immediately in an expedited manner according to section 8.3. If there is 
any uncertainty whether the intervention is a contributing factor to the event, the event should be 
reported as AE or SAE as appropriate.
8.5
REPORTING PREGNANCY 
All required pregnancy reports/follow-up to OSRO will be submitted to: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator. 
Forms and instructions can be found here: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions 
8.5.1
Maternal Exposure
If a participant becomes pregnant while actively on study intervention, the study intervention 
should be discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 
hours of when the Investigator becomes aware of it. The Investigator should notify the Sponsor 
no later than 24 hours of when the outcome of the Pregnancy becomes known.
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects 
and spontaneous miscarriages that meet serious criteria (section 8.1.2) should be reported as 
SAEs. 
The outcome of all pregnancies should be followed up and documented.
8.5.2
Paternal Exposure
Male participants should refrain from fathering a child or donating sperm during the study and 
for 2 months after the last dose of 18F-DCFPyL.
Pregnancy of the participant’s partner is not considered to be an AE. The outcome of all 
pregnancies occurring from the date of the first dose until 2 months after the last imaging should, 

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if possible, be followed up and documented. Pregnant partners may be offered the opportunity to 
participate in an institutional pregnancy registry protocol (e.g., the NIH IRP pregnancy registry 
study) to provide data about the outcome of the pregnancy for safety reporting purposes.
8.6
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR SPONSORED IND
Following notification from the investigator, CCR, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected. CCR will report an AE as a suspected 
adverse reaction only if there is evidence to suggest a causal relationship between the study 
product and the adverse event. CCR will notify FDA and all participating investigators (i.e., all 
investigators to whom the sponsor is providing drug under its INDs or under any investigator’s 
IND) in an IND safety report of potential serious risks from clinical trials or any other source, as 
soon as possible, in accordance to 21 CFR Part 312.32. 
All serious events will be reported to the FDA at least annually in a summary format.
8.7
SPONSOR PROTOCOL DEVIATION REPORTING 
A Protocol Deviation is defined as any non-compliance with the clinical trial Protocol, Manual 
of Operational Procedures (MOP) and other Sponsor approved study related documents, GCP, or 
protocol-specific procedural requirements on the part of the participant, the Investigator, or the 
study site staff inclusive of site personnel performing procedures or providing services in support 
of the clinical trial.
It is the responsibility of the study Staff to document any protocol deviation identified by the 
Staff or the site Monitor in the CCR Protocol Deviation Tracking System (PDTS) online 
application. The entries into the PDTS online application should be timely, complete, and 
maintained per CCR PDTS user requirements. 
In addition, any deviation to the protocol should be documented in the participant’s source 
records and reported to the reviewing IRB per their guidelines. OSRO required protocol 
deviation reporting is consistent with E6(R2) GCP: Integrated Addendum to ICH E6(R1): 4.5 
Compliance with Protocol; 5.18.3 (a), and 5.20 Noncompliance; and ICH E3 16.2.2 Protocol 
deviations.
9
CLINICAL MONITORING PLAN
Clinical site monitoring is conducted to ensure:

that the rights of the participants are protected; 

that the study is implemented per the approved protocol, Good Clinical Practice and 
standard operating procedures; and, 

the quality and integrity of study data and data collection methods are maintained. 
Monitoring for this study will be performed by NCI CCR Office of Sponsor and Regulatory 
Oversight (OSRO) and Regulatory Oversight Support (SROS) Services contractor. Clinical site 
monitoring activities will be based on OSRO standards, FDA Guidance E6(R2) Good Clinical 
Practice: Integrated Addendum to ICH E6(R1) March 2018, and applicable regulatory 
requirements.

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Details of clinical site monitoring will be documented in a Clinical Monitoring Plan (CMP) 
developed by OSRO. CMPs will be protocol-specific, risk-based and tailored to address human 
subject protections and integrity of the study data. OSRO will determine the intensity and 
frequency of monitoring based on several factors, including study type, phase, risk, complexity, 
expected enrollment rate, and any unique attributes of the study and the site. The Sponsor will 
conduct a periodic review of the CMP to confirm the plan's continued appropriateness. A change 
to the protocol, significant or pervasive non-compliance with GCP, or the protocol may trigger 
CMP updates.
OSRO SROS Monitoring visits and related activities will be conducted throughout the life cycle 
of each protocol. The first activity is before the study starts to conduct a Site Assessment Visit 
(SAV) (as warranted), followed by a Site Initiation Visit (SIV), Interim Monitoring Visit(s) 
(IMVs), and a study Close-Out Visit (COV).
Some monitoring activities may be performed remotely, while others will occur at the study 
site(s). Monitoring visit reports will describe visit activities, observations, and associated action 
items or follow-up required for resolution of any issues, discrepancies, or deviations. Monitoring 
reports will be distributed to the study PI, NCI CCR QA, CCR Protocol Support Office, 
coordinating center (if applicable), and the Sponsor regulatory file.
The site Monitor will inform the study team of any deviations observed during monitoring visits. 
If unresolved, the Monitor will request that the site Staff enter the deviations in the CCR 
Protocol Deviation Tracking System (PDTS) for deviation reporting to the Sponsor and as 
applicable per institutional and IRB guidance.
10 STATISTICAL CONSIDERATIONS 
10.1 PRIMARY ENDPOINT
18F-DCFPyL PET/CT will be used to identify positive suspected sites, which will be correlated 
with histopathology results. For lesions within the liver, a focal abnormal area of increased 18F-
DCFPyL activity higher than the surrounding liver uptake (SUVmax more than x 1.2 times than 
the normal liver-SUV mean) will be considered positive. For lesions outside the liver, a positive 
lesion is defined as focal abnormal uptake higher than the blood pool, or the surrounding normal 
organ or soft tissue background. Pathological anatomic imaging but lacking DCFPyL uptake 
would indicate a type of tumor that fails to express PSMA. The performance of 18F-DCFPyL 
PET/CT is assessed by the positive predictive value which is defined as the proportion of 
histopathology positive lesions. 
10.2 SECONDARY ENDPOINTS 

Compare the lesion level sensitivity, specificity and positive predictive value of 18F-
DCFPyL PET/CT with standard CT and/or MRI imaging, and 18F-FDG PET/CT.

Compare 18F-DCFPyL PET/CT uptake between pre- and post-treatment in 18F-DCFPyL 
PET/CT positive participants (as measured by change in pre-treatment and post-treatment 
SUV) to detect treatment response following local treatment. 

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10.3 EXPLORATORY ENDPOINTS 

Correlate the intensity of uptake of 18F-DCFPyL PET/CT with respect to the CT and/or 
MRI tumor grade.

Correlate tumor tissue histological PSMA expression with the intensity of uptake of 18F-
DCFPyL PET/CT.

Compare tumor viability and metabolism determined by 18F-FDG PET imaging with 18F-
DCFPyL uptake.

18F-DCFPyL intensity of uptake (expressed as the maximum standard uptake value – 
SUVmax) and tumor volume will be correlated with 5 year overall survival, and 5 year 
progression free survival.

Evaluate tumor biomarkers in blood, urine and tissue samples.
10.4 SAMPLE SIZE DETERMINATION
Sample size was calculated such that the limits of the 95% expected confidence interval to the 
true lesion level positive predicted value is less than 15%. The lesion level positive predictive 
value is the proportion of biopsy positive lesions. Assume 80% of the participants enrolled to the 
study each have 1-2 lesions identified by 18F-DCFPyL PET/CT with 0.2 modest inter-lesion 
correlation, and the positive predictive value is 70%. A sample size of 40 evaluable participants 
accrued to the study produces a two-sided 95% confidence interval with the distance from the 
positive predictive value to the limits equal to 0.148. An evaluable participant is defined as a 
participant who completes all required study procedures. To account for inevaluable participants, 
the accrual ceiling will be set to 50. 
10.5 ANALYSIS OF THE PRIMARY ENDPOINT
The point estimates and 95% confidence intervals of the positive predictive value of 18F-
DCFPyL PET/CT will be reported in which the confidence limits are the 2.5th and 97.5th 
percentile of the 2000 bootstrap samples obtained by random sample without replacement at the 
participant level to account for inter-lesion correlation. 
10.6 ANALYSIS OF THE SECONDARY ENDPOINTS

The lesion level sensitivity, specificity and positive predictive value of 18F-DCFPyL 
PET/CT and CT/MRI will be calculated and compared. The confidence interval for each 
estimate will be obtained from the bootstrap samples as described in 10.5 and the 
difference in the estimates between the imaging modalities will be compared by the Wald 
test with the standard error calculated from the bootstrap samples. 

For 18F-DCFPyL PET/CT positive participants who undergo local treatment for HCC, 
change in 18F-DCFPyL PET/CT uptake between pre- and post-treatment of tumor or 
tumor bed will be compared by paired Wilcoxon test.
10.7 ANALYSIS OF EXPLORATORY ENDPOINTS

The uptake of 18F-DCFPyL PET/CT will be correlated with CT/MRI grade by Kendall’s 
tau-b correlation.

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
The uptake of 18F-DCFPyL PET/CT will be correlated with tumor tissue histological 
PSMA expression by Kendall’s tau-b correlation.

The uptake of 18F-DCFPyL PET/CT measured by maximum Standard Uptake Value 
(SUV) will be correlated with 18F-FDG uptake by Spearman rank correlation. These SUV 
uptake measurements will also be correlated with PSMA expression as determined by 
standard histological assessment of tumor tissue. 

Uptake of 18F-DCFPyL PET/CT with be correlated with 5 year progression free survival 
(via scans collected from local providers during routine follow up) and 5 year overall 
survival by Cox regression analysis. 

Descriptive statistics will be used to summarize tumor biomarkers in blood and tissue 
samples.
10.8 INTERIM FUTILITY ANALYSIS AND EARLY STOPPING RULE
To avoid excessive expense and radiation exposure, if 18F-DCFPyL PET/CT is not successful in 
identifying lesions, we will implement the following interim futility analysis and early stopping 
rule.
We plan to stop the protocol if the first 5 participants with lesions greater than 1 cm have 
negative DCFPyL uptake (defined as tumor uptake less than adjacent background soft tissue, or 
less than blood pool for lymph nodes). 
11 COLLABORATIVE AGREEMENTS 
11.1 TRANSFERS ASSOCIATED WITH CORRELATIVE STUDIES CONDUCTED UNDER AN APPROVED 
PROTOCOL 
Investigators in the NIH intramural program may participate in multi-site clinical trials (either as 
a site or as the coordinating center) under which human materials are transferred from the 
intramural program to another site for correlative studies that are part of the approved protocol. 
In such a situation, the protocol clearly documents the tests conducted under the correlative 
studies, and each institution participating in the clinical study is bound by the terms of their 
Protocol and their obligations under the statutes and regulations. In addition, intramural protocols 
are cleared by the IC Clinical Director. In such situations, use of an HM-MTA is not necessary 
for these transfers.
11.2 MULTI-INSTITUTIONAL GUIDELINES
11.2.1 IRB Approvals 
The PI will provide the NIH Intramural IRB with a copy of the participating institution’s initial 
approval and approved yearly continuing review. 

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12 HUMAN SUBJECTS PROTECTIONS 
12.1 RATIONALE FOR SUBJECT SELECTION
All participants with HCC meeting eligibility criteria may participate in this study. Individuals of 
any race, ethnic group, or gender will be eligible for this study. Physically impaired persons who 
otherwise satisfy eligibility criteria will be included in this study. 
12.2 PARTICIPATION OF CHILDREN
Children will not be considered as research subjects for this study as 18F-DCFPyL dosing and 
toxicity has not been established in this population.
12.3 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS
12.3.1 Risk/Benefit Assessment
12.3.1.1 Known Potential Risks
12.3.1.2 Risks related to 18F-DCFPyL
The risks related to 18F-DCFPyL include radiation exposure allergic reaction, fatigue, dysgeusia, 
and headache. 
12.3.1.3 Risks related to 18F-FDG
Risks associated with 18F-FDG include radiation and hypersensitivity reaction.
12.3.1.4 Risks related to IV
The risks associated with IV include temporary pain, bleeding and bruising at the infusion site, 
leakage of 18F-DCFPyL and 18F-FDG into the skin and tissue around the IV and infection.
12.3.1.5 Risks related to PET/CT scan
The risks associated PET/CTs include IV insertion site pain, bruising, dizziness, hypotension, 
inflammation of the vein or infection at the needle site. Other side effects could include 
discomfort from lying on a hard surface for an extended period and infection at the IV site or 
blood.
12.3.1.5.1 Risks of exposure to Ionizing Radiation 
This research study involves exposure to radiation from up to 3 18F-DCFPyL PET/CTs, 3 
regional CTs of a single field-of-view including the liver lesion (for the dynamic portion of the 
18F-DCFPyL PET/CT), up to 3 18F-FDG PET/CTs, up to 3 chest/abdomen/pelvis CTs, and 2 CT-
guided biopsies. The amount of radiation exposure from these procedures is equal to 
approximately 12.6 rem. This amount is more than would be expected from everyday 
background radiation. Being exposed to excess radiation can increase the risk of cancer. The risk 
of getting cancer from the radiation exposure in this study is 1.3 out of 100 (1.3%) and of getting 
a fatal cancer is 0.6 out of 100 (0.6%).
Note: dosimetry estimates are based on NIH scanners. Estimates at participating sites may vary.

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12.3.1.6 CT contrast risk
Itching, hives, shortness of breath, shock and rarely death are possible risks associated with 
contrast agents that may be used during CT imaging. Very rarely, the contrast agents used in CT 
can cause kidney problems for certain participants, such as those with impaired kidney function.
12.3.1.7 MRI and MRI Contrast Risks 
Participants are at risk for injury from the MRI magnet if they have metal in their body. There is 
a possibility that participants may experience claustrophobia. There are risks of back discomfort 
related to lying in the scanner. 
The most common side effects from MRI contrast (gadolinium) include injection site pain, 
metallic taste, nausea, hives, headaches, difficulty breathing, hypotension and an allergic 
reaction. Serious but rare side effects such as gadolinium toxicity and nephrogenic systemic 
fibrosis, or NSF, are most often seen in patients with severe kidney problems.
The risks of an IV catheter include bleeding, infection, or inflammation, pain and swelling of the 
skin and vein. 
12.3.1.8 Risks of Blood Draw 
Side effects of blood draws include pain and bruising in the area where the needle was placed, 
lightheadedness, and rarely, fainting. Up to 17 mL of blood maybe collected at each study visit 
when a 18F-DCFPyL PET/CT occurs. Up to 7 mL of blood may be collected at each follow-up 
visit.
12.3.1.9 Risk of Biopsy
All care will be taken to minimize risks that may be incurred by tumor sampling. Procedure-
related risks include pain, bleeding, tenderness, scarring, and infection. Complications from 
biopsies may be life threatening and may include organ damage.
There is a possibility that conscious sedation may be used for the procedure. The common side 
effects of conscious sedation include drowsiness, delayed reflexes, hypotension, headache, and 
nausea. These are generally mild and last no more than a few hours. 
12.3.1.10 Risk from Urine Collection
There are no known risks associated with urine collection.
12.3.1.11 Known Potential Benefits
There are no direct benefits to the study participant; however, the study results may help the 
investigators learn more about the effectiveness of 18F-DCFPyL imaging in identifying sites of 
HCC and could help confirm treatment success.
12.4 CONSENT PROCESS AND DOCUMENTATION
The informed consent document will be provided as a physical or electronic document to the 
participant as applicable for review prior to consenting. A designated study investigator will 
carefully explain the procedures and tests involved in this study, and the associated risks, 
discomforts and benefits. In order to minimize potential coercion, as much time as is needed to 
review the document will be given, including an opportunity to discuss it with friends, family 

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members and/or other advisors, and to ask questions of any designated study investigator. A 
signed informed consent document will be obtained prior to entry onto the study.
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with 
local policy, and/including HRPP Policy 303) per discretion of the designated study investigator 
and with the agreement of the participant. Whether in person or remote, the privacy of the 
subject will be maintained. Consenting investigators (and participant, when in person) will be 
located in a private area (e.g., clinic consult room). When consent is conducted remotely, the 
participant will be informed of the private nature of the discussion and will be encouraged to 
relocate to a more private setting if needed. 
Consent will be documented with required signatures on the physical document (which includes 
the printout of an electronic document sent to participant) or on the electronic document, with a 
manual (non-electronic) signature on the electronic document. When required, witness signature 
will be obtained similarly as described for the investigator and participant.
 Please see site specific supplement for electronic signature requirements for each site.
13 REGULATORY AND OPERATIONAL CONSIDERATIONS 
13.1 STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, 
investigator, funding agency, the Investigational New Drug (IND) sponsor and regulatory 
authorities. If the study is prematurely terminated or suspended, the Principal Investigator (PI) 
will promptly inform study participants, the Institutional Review Board (IRB), and sponsor and 
will provide the reason(s) for the termination or suspension. Study participants will be contacted, 
as applicable, and be informed of changes to study visit schedule.
Circumstances that may warrant termination or suspension include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to participants

Demonstration of efficacy that would warrant stopping 

Insufficient compliance to protocol requirements

Data that are not sufficiently complete and/or evaluable

Determination that the primary endpoint has been met

Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and as applicable, Food and Drug Administration (FDA).
13.2 QUALITY ASSURANCE AND QUALITY CONTROL
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion. An individualized quality management plan 
will be developed to describe a site’s quality management.

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Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, International Council on 
Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., 
Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities.
13.3 CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed 
and managed. Furthermore, persons who have a perceived conflict of interest will be required to 
have such conflicts managed in a way that is appropriate to their participation in the design and 
conduct of this trial. The study leadership in conjunction with the NCI has established policies 
and procedures for all study group members to disclose all conflicts of interest and will establish 
a mechanism for the management of all reported dualities of interest.
13.4 CONFIDENTIALITY AND PRIVACY
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the participants in this study. The 
clinical study site will permit access to such records.
The study participant’s contact information will be securely stored at the/each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or 
sponsor requirements.
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be stored at the NCI CCR. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be identified 
by a unique study identification number. The study data entry and study management systems 

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used by the clinical site(s) and by NCI CCR research staff will be secured and password 
protected. At the end of the study, all study databases will be archived at the NIH.
To further protect the privacy of study participants, a Certificate of Confidentiality has been 
issued by the National Institutes of Health (NIH). This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any 
civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or 
local level. By protecting researchers and institutions from being compelled to disclose 
information that would identify research participants, Certificates of Confidentiality help achieve 
the research objectives and promote participation in studies by helping assure confidentiality and 
privacy to participants.
14 PHARMACEUTICAL INFORMATION/COMMERCIAL IMAGING 
14.1
18F-DCFPYL (IND: 133631)
14.1.1 Source/Acquisition and Accountability 
14.1.1.1 Agent Ordering
18F-DCFPyL will be ordered from NIH PET department. MIB staff will contact the 
radiopharmacy, a date and time will be assigned, and an order placed with the radiopharmacy 
using the NIH Supply ordering system for Radiopharmaceuticals. http://supply.cc.nih.gov/.
14.1.1.2 Agent returns
The investigator or appropriate investigator-designee will order subject doses of the IND agent 
for this specific trial. The investigational radiopharmaceutical will be shipped to the site on the 
day the participant is to be injected, taking into account varying radioactive half-lives for 
different radioactive imaging agents. 
14.1.1.3 Agent Inventory Records
If for any reason the study imaging is unable to be completed, sites will allow the radioactivity of 
the 18F-DCFPyL solution to decay and then discard it appropriately per site’s policies and 
procedures, making a record of the event as required. A copy of the policy should be available 
upon request.
14.1.2 Toxicity 
Refer to section 1.2.2.
14.1.3 Formulation and Preparation 
No preparation required by study staff and/or study participants. The 18F-DCFPyL used in this 
study is prepared in the PET Department CC/NIH. 18F-DCFPyL for each study participant will 
be received in individual participant doses from the PET department. Containers that are 
radioactive or contain radioactive products will be disposed of per NIH Radiation Safety 
Guidelines.
Manufacture of 18F-DCFPyL drug substance and formulation, sterilization and filling of 18F-
DCFPyL Injection drug product, is a continuous process whereby the drug substance is never 

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isolated or held. Immediately upon completion of the radiosynthesis reaction that forms 18F-
DCFPyL drug substance, the reaction mixture is purified by high performance liquid 
chromatography and formulated in a solution of Sodium Chloride Injection (0.9%) containing 
ethanol. A sample is removed for analytical testing under aseptic conditions for chemical and 
radiochemical quality control analysis, and bacterial endotoxin and sterility testing. This 
completes the manufacture of 18F-DCFPyL injection. The lowest limit for specific-activity (SA) 
that will be used at the time of injection is 1000 mCi/µmole, although the validation and phase I 
study radiosynthesis SA was significantly higher than 1000 mCi/µmole. 
14.1.4 Stability and Storage 
The in-use shelf-life of 18F-DCFPyL will be specified on the label. Although from a chemical 
perspective, the product remains stable beyond 6 hours, due to the short 109.8-minute half-life of 
18F, the low level of activity present after 6 hours renders it unsuitable for positron imaging 
tomography studies. 18F-DCFPyL is stored in the original container at 4 °C under inert 
atmosphere.
14.1.5 Administration Procedures
Refer to section 3.2. 
14.2
18F-FDG (IND: 133631)
For complete information, refer to package insert.
14.2.1 Source/Acquisition and Accountability 
Commercial supplies of 18F-FDG will be purchased for use in this study.
14.2.2 Administration Procedures
Refer to section 3.2.3.
 

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16 APPENDICES
16.1 APPENDIX A - PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Grade
Descriptions
0
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair.
5
Dead.