Conditions: Lung Carcinoma Solitary Pulmonary Nodule Cigarette Smoking Behavior
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 46
Healthy volunteers: no

Brief summary:
This clinical trial compares fluorine F 18 L-glutamate derivative BAY94-9392 (18F-FSPG) positron emission tomography (PET)/computed tomography (CT) to the standard of care fluorodeoxyglucose F-18 (18F-FDG) PET/CT in imaging patients with newly diagnosed lung cancer or indeterminate pulmonary nodules. PET/CT uses a radioactive glutamate (one of the common building blocks of protein) called 18F-FSPG which may be able to recognize differences between tumor and healthy tissue. Since tumor cells are growing, they need to make protein, and other building blocks, for cell growth that are made from glutamate and other molecules. PET/CT using a radioactive glutamate may be a more effective method of diagnosing lung cancer than the standard PET/CT using a radioactive glucose (sugar), such as 18F-FDG.

Detailed description:
PRIMARY OBJECTIVES:

I. To compare the imaging characteristics of 18F-FSPG PET/CT with standard-of-care, 18F-FDG PET/CT.

II. To compare the imaging characteristics of 18F-FSPG PET/CT to standard-of-care 18F-FDG PET/CT in patients with newly diagnosed lung cancer.

III. To determine whether 18F-FSPG uptake in lung cancer can be predicted based on correlation with CD44 and amino acid transport system xc- (xC-) expression in surgical pathology specimens.

OUTLINE:

Patients undergo 18F-FDG PET/CT scan per standard of care. Within 15 working days, patients also undergo 18F-FSPG PET scan over 60 minutes followed by an 18F-FSPG PET/CT scan over 30 minutes.

After completion of study, patients are followed up for 2 years if needed for diagnosis.

Arms:
arm 1: Patients undergo 18F-FDG PET/CT scan per standard of care. Within 15 working days, patients also undergo 18F-FSPG PET scan over 60 minutes followed by an 18F-FSPG PET/CT scan over 30 minutes.

Interventions: intervention 1: Computed Tomography intervention 2: Computed Tomography intervention 3: fluorodeoxyglucose F-18 intervention 4: Fluorine F 18 L-glutamate Derivative BAY94-9392 intervention 5: Laboratory Biomarker Analysis intervention 6: Positron Emission Tomography intervention 7: Positron Emission Tomography (PET)
Intervention descriptions: intervention 1: Undergo 18F-FDG PET/CT - standard of care intervention 2: Undergo 18F-FSPG PET/CT intervention 3: Undergo 18F-FDG PET/CT - standard of care intervention 4: Undergo 18F-FSPG PET/CT intervention 5: Correlative studies intervention 6: Undergo 18F-FDG PET/CT - standard of care intervention 7: Undergo 18F-FSPG PET/CT

Protocol document:
Prot_SAP_000.pdf: 
THO 1524: [18F]FSPG PET Protocol 
Protocol Date: 10/03/2019 
1 
THO 1524: PET Imaging of Lung Cancer and Indeterminate Pulmonary Nodules with 18F-FSPG 
Ver 9: 04/06/2021 
Sponsor- Investigator 
Chirayu Shah, MD 
Ingram Professor of Cancer Research 
Division of Allergy Pulmonary and Critical Care Medicine 
Vanderbilt University Medical Center 
Nashville, TN 
Statistician 
Heidi Chen, PhD 
Associate in Biostatistics, Division of Cancer Biostatistics 
Vanderbilt-Ingram Cancer Center 
Vanderbilt University Medical Center, Nashville, TN 
Additional Site 
Tennessee Valley Health System Nashville 
Site Principal Investigator Chirayu Shah, MD 


THO 1524: [18F]FSPG PET Protocol 
 
 
 
 
 
 
 
Protocol Date: 10/03/2019 
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Table of Contents 
1. Background ..................................................................................................... 3 
2. Objectives, Rationale, and Specific Aims ..................................................... 8 
3. Animal Studies and Previous Human Experience ....................................... 9 
4. Patient Eligibility & Inclusion / Exclusion Criteria ..................................... 10 
A. INCLUSION CRITERIA ............................................................................................................10 
B. EXCLUSION CRITERIA ...........................................................................................................10 
5. Enrollment/Randomization........................................................................... 11 
PATIENT REGISTRATION ...........................................................................................................12 
6. Data Management and Monitoring .............................................................. 12 
7. Study Procedures & Data Collection ........................................................... 13 
BASELINE IMAGING: CT ...........................................................................................................13 
IMAGING PROTOCOL: 18F-FSPG (FIGURE 1) ...........................................................................13 
RADIOTRACER PRODUCTION ....................................................................................................15 
18F-FSPG PET PROCEDURE AND DYNAMIC DATA ANALYSIS .................................................15 
CLINICAL DATA ANALYSIS........................................................................................................15 
RATIONALE FOR SIZE CRITERIA ...............................................................................................16 
8. Risks 
 ...................................................................................................... 18 
RADIOPHARMACEUTICAL ..........................................................................................................18 
INJECTION ..................................................................................................................................18 
REPRODUCTIVE RISK ................................................................................................................18 
DOSE RATIONALE ......................................................................................................................18 
RADIATION SAFETY ...................................................................................................................18 
TOXICITY STUDIES ....................................................................................................................19 
9. Reporting of Adverse Events or Unanticipated Risks to Participants or 
Others 
 ...................................................................................................... 19 
SERIOUS ADVERSE EVENTS (SAE) ARE DEFINED IN ACCORDANCE WITH THE NCI’S CTCAE 
VER. 4.0. ...................................................................................................................................................20 
10. Study Withdrawal / Discontinuation .......................................................... 21 
11. Statistical Considerations .......................................................................... 21 
STUDY DESIGN ...........................................................................................................................21 
SAMPLE SIZE AND STUDY POWER .............................................................................................22 
DATA ANALYSIS .........................................................................................................................22 
12. Privacy / Confidentiality ............................................................................. 23 
13. Follow-up and Record Retention ............................................................... 23 
STUDY PROCEDURE CALENDAR (2-YEAR FOLLOW-UP BY CT ONLY NEEDED FOR SUBJECTS 
WITHOUT A DEFINITIVE DIAGNOSIS OF THE NODULE OR MASS BY BIOPSY) ...........................................24 
14. References................................................................................................... 25 
 


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1. Background 
 
Lung Cancer and Indeterminate Pulmonary Nodules (IPNs): The estimated number of patients 
with newly diagnosed lung cancer in the US for 2013 is 228,190 (118,080 men and 110,110 
women), with an estimated 159,480 deaths (87,260 men, 72,220 women). Lung cancer now is, 
and will be for years to come, the leading cause of cancer death in both the US and the world. The 
five-year relative cancer survival of all stages and all types combined (2002-2008) ranges from 
17% for lung cancer to nearly 100% for prostate cancer (1). The future U.S. cancer burden, 
estimated from the current and projected size and age demographics of the U.S. population, is 
expected to more than double from 1.4 million in 2000 to almost 3.0 million in 2050. The lifetime 
risk of developing cancer of the lung/bronchus is 1 in 12 for men and 1 in 16 for women (2). The 
primary risk factor for lung cancer is smoking, with the percentage of the southeastern US 
population estimated to be smokers significantly higher than for the general US population, with 
correspondingly higher incidence and death rates from all tobacco-related cancers. 
 
Two contributors to the high mortality of lung cancer are the frequent advanced stage of the 
disease when discovered and the delay in diagnosis of cancer in a newly discovered IPN. This delay 
in definitive diagnosis of an IPN can potentially allow time for metastasis to occur during the 
follow-up interval. The exciting results of the National Lung Screening Trial (NLST) demonstrated 
an approximately 20% reduction in lung cancer specific mortality via low-dose computed 
tomography (LDCT) screening of high-risk patients. As a result, the US Preventive Services Task 
Force has recommended annual LDCT screening for an estimated 7.4 million Americans at high 
risk for lung cancer (3). However, even in high-risk patients, most IPNs were benign. Specifically, 
24.2% of LDCT screening scans had IPNs requiring further evaluation (usually serial CTs for up to 
2 years), with 96.4% of these positive screening CTs eventually found to be false positive (4). 
Furthermore, 8.3% of all positive scans had a subsequent 18F-FDG PET/CT scan as part of the 
diagnostic process. Since IPNs in high risk patients must be followed with serial LDCT exams (5), 
and guidelines suggest diagnosis with 18F-FDG-PET/CT scans for lesions larger than 8 mm that have 
a greater than a 5% likelihood of cancer (6), patients may receive up to 5 additional LDCT scans, 
and possibly an 18F-FDG PET/CT scan, to follow an IPN.  These subsequent scans are at 
considerable time/expense to both the patient and the healthcare system, when over 96% of 
these nodules will be benign. The economic burden of this disease is staggering. The annual cost 
of >150,000 deaths/y in the US from lung cancer is >$12 billion (7). The estimated cost of lung 
cancer screening in the US is up to $2 billion/y. The subsequent management of IPNs, requiring 
serial CT scans, and sometimes invasive biopsies or surgical resection, is estimated to be many 
times greater, perhaps as much as $240,000 per additional lung cancer death avoided, when 
allowing for the costs of no screening and overdiagnosis (8). 
 
Disease Management: One management option for newly diagnosed indeterminate lung nodules 
is “watchful waiting” to see if the nodule increases in size over a two-year period, with the obvious 
caveat that during this time cells from a malignant nodule could metastasize, resulting in the lost 
chance of a cure. The other option, proceeding to tissue diagnosis at the time of discovery, is often 
inappropriate for several reasons. While bronchoscopy with brush cytology or transbronchial 
biopsy may be useful if the lesion is 2 cm or larger in size, the reported diagnostic yield of 
bronchoscopy for a solitary pulmonary nodule varies widely in the literature (20-80%) and 
depends on the size of the nodule, the incidence of malignancy in the study population, and the 
skill of the operator. Transthoracic fine needle aspiration biopsy can also be considered for lung 


THO 1524: [18F]FSPG PET Protocol 
 
 
 
 
 
 
 
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nodules, but is most useful in nodules with a diameter of at least 2 cm. False negative results, 
occurring in up to 30% of the patients, remain a serious clinical problem. Unfortunately, the 
success rate of diagnosis is inversely related to nodule size, and yet the greatest hope for cure lies 
in detecting cancer as early as possible, presumably in smaller nodules. Thus, a definitive biopsy 
often requires surgical resection, via video-assisted thoracoscopic surgery (VATS) or open 
thoracotomy, since less invasive techniques have unacceptably high false negative rates (9-11). 
 
Therapy: Resection of early stage disease remains the only proven means to improve long-term 
survival from lung cancer. Although the smoking rate in the US is decreasing, it remains 
unacceptably high. The risk of lung cancer accordingly will remain elevated for many years due to 
smoking prevalence, general demographics, and potential exposure to other inhaled carcinogens 
(1). Additionally, now that lung cancer screening of high risk individuals is adopted in the US, the 
capacity of the US Healthcare System is severely strained to meet demand. Nonetheless, low-dose 
annual CT screening for lung cancer in high-risk patients is the only proven means to reduce lung 
cancer deaths, with a 20% reduction in cancer-specific mortality (4). 
 
The US Preventative Services Task Force has endorsed LDCT lung cancer screening for high risk 
patients as an effective means of reducing lung cancer deaths, with a “B” level recommendation, 
equal to that of screening mammography. Thus, most US medical facilities already offer low-dose 
lung cancer screening programs (12), and both medical and public advocacy societies have 
endorsed lung cancer screening, including the American Cancer Society, American College of 
Chest Physicians, American College of Radiology, American Society of Clinical Oncology, the 
National Comprehensive Cancer Network (NCCN), the American Lung Association and others (13). 
In 2015, the Center for Medicare and Medicaid Services (14) began to reimburse LDCT in high-risk 
patients within the Medicare population. It is estimated that approximately four million Medicare 
beneficiaries fit the eligibility criteria for screening, which includes adults age 55 to 74 who have 
a thirty pack/year smoking history and are either currently smoking or have quit in the past 15 
years (14). While the specific number of lives saved annually in the US by lung cancer screening 
will be affected by the adherence to the screening protocol, prevalence of lung cancer in the local 
screened population, and the effectiveness of associated smoking-cessation programs, the 
number is estimated to be about 12,000 annually (15). In addition, under the Affordable Care Act, 
private medical insurance is required to cover lung cancer screening with no co-pay as of 2015. 
Accordingly, the number of new IPNs discovered annually in the US will increase several fold, 
reaching into the millions. Clearly the management of IPNs in the US population is a complex and 
resource-intensive task. As the US Healthcare System increasingly adopts lung cancer screening, 
improved means of managing IPNs will be urgently needed. 
 
Positron emission tomography (PET) imaging in lung cancer: Imaging with computed 
tomography (CT) (either at a single time point or serially over time) or with positron emission 
computed tomography combined with CT (PET/CT) can help to discriminate between benign and 
malignant nodules, yet the best image-based methods are also inexact, with both false positive 
(FP) and false negative (FN) results leading to unnecessary surgery or missed early diagnosis, 
respectively. Collective experience with the most widely used PET tracer in oncology, 2-deoxy-2-
(18F)-fluoro-D-glucose (18F-FDG), a probe that measures glucose utilization, has been variable. 18F-
FDG PET possesses limited ability to discriminate between benign and malignant lung nodules less 
than 1 cm in diameter, as well as limited value in relatively quiescent lung cancers, such as well-
differentiated adenocarcinoma or typical carcinoid tumors (16). The sensitivity of PET scanning 


THO 1524: [18F]FSPG PET Protocol 
 
 
 
 
 
 
 
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for small lesions drops significantly to around 60% (17). In lesions smaller than 1 cm, only very 
intense 18F-FDG uptake is clearly perceived. Nomori, et al. (18), examined 136 nodules smaller 
than 3 cm in diameter. All 20 nodules smaller than 1 cm were negative on standard-of-care 18F-
FDG PET, eight (40%) of which were malignant. This problem is compounded by false positive (FP) 
uptake of 18F-FDG in IPNs. Much of the US population lives in areas with endemic fungal disease, 
such as histoplasmosis, coccidioidomycosis and cryptococcus. Vanderbilt University Medical 
Center (VUMC) is in the Ohio/Mississippi river valley complex, where coccidiomycosis and 
histoplasmosis are particularly common. Other large segments of the US population are in other 
areas of endemic fungal disease, such as the entire southwestern US, including southern 
California. In our prospective analysis of 211 patients referred to our thoracic oncology, thoracic 
surgery and/or pulmonary medicine services, the sensitivity of 18F-FDG PET/CT was good (92%) 
but the specificity was only 40%, with 60% of benign nodules having FP uptake (19). Nearly 
identical results were reported from another location in the Ohio/Mississippi river valley complex 
by Croft, et al. at the University of Iowa (20). 
 
Highly proliferative cells, as found in most lung cancers, utilize Warburg metabolism to both 
provide energy and building blocks needed for cellular proliferation. This is an effect shared with 
all proliferating eukaryotic cells, but particularly expressed in aggressive malignancies, providing 
the target of metabolism exploited with 18F-FDG PET/CT. Unfortunately, other non-malignant cells 
with high glucose consumption, such as macrophages, particularly found in granulomatous 
nodules, also have high uptake of 18F-FDG (21). These two factors often lead to the “false positive” 
uptake on 18F-FDG PET/CT scans in areas of endemic fungal and other granulomatous nodules 
(22). This, of course, explains the high sensitivity of 18F-FDG PET/CT imaging of IPNs, along with its 
poor specificity (~40%), observed in many areas of the US. 
 
Patients with newly discovered IPNs (often by “accident” when an x-ray or CT scan is performed 
for an unrelated reason) may be at high risk for lung cancer. Patients with IPNs or lung cancer 
typically have a significant smoking history, are often current smokers, and commonly have other 
tobacco-related co-morbidities such as COPD, emphysema and/or cardiovascular disease that 
greatly impair their functional status and confer high risk for interventional procedures needed to 
establish a definitive diagnosis. 
 
Differentiation of a benign from a malignant lung nodule is imperfect at the time of IPN discovery. 
No combination of CT characteristics can definitively determine if a given IPN is benign or 
malignant (23, 24). While 
18F-FDG PET/CT is helpful, it can be confounded by 
infection/inflammation, small nodule size, metabolically indolent cancers, and ground-glass or 
part-solid nodules. Moreover, in much of the United States, a variety of fungi and other 
granulomatous processes confound CT further, with most of the tracer uptake in active 
granulomatous nodules relegated to inflammatory stroma. Therefore, an improved means to 
discriminate benign from malignant IPNs at the time of discovery is badly needed. 
 


THO 1524: [18F]FSPG PET Protocol 
 
 
 
 
 
 
 
Protocol Date: 10/03/2019 
6 
Other PET probes have been tried, particularly in animal models of lung cancer, but none match 
the superior sensitivity of 18F-FDG. Given the life-threatening nature of lung cancer, and the 
number of IPNs seen on CT, we have a great 
need to improve upon the 40% specificity of 18F-
FDG PET/CT for diagnosis of lung nodules in 
regions of endemic granulomatous infections, 
yet 
without 
sacrificing 
18F-FDG’s 
~90% 
sensitivity, particularly in the context of 
nationwide lung cancer screening. 
 
Figure 1.  A Diagnostic PET Tracer of Cancer 
Cell Metabolism (18F-FSPG): Tumor cells adopt 
distinct metabolic pathways to ensure a 
sufficient supply of energy and building blocks 
for growth and proliferation. There is 
emerging evidence for the existence of a 
tumor-specific truncated tricarboxylic acid 
cycle (25) associated with a high rate of 
lipogenesis and glutaminolysis from glutamine 
and glutamate (26). As a result of the 
truncated TCA cycle, glutamine and glutamate are often major metabolic substrates of tumor 
cells in parallel or even instead of glucose-derived metabolites like pyruvate. Targeting those 
tumor-specific pathways with 18F-labeled tracers represents a promising approach for 
improved PET imaging of tumors. 
 
(S)-4-(3-[18F]-fluoropropyl)-L-glutamic acid (18F-FSPG) is a new 18F-labeled radiotracer designed for 
positron emission tomography (PET) imaging of tumors (Fig. 1). 18F-FSPG (originally [18F]BAY 94-
9392) is an 18F-labeled glutamic acid derivative originally identified to target tumor-specific 
adaptations of intermediary metabolism. 18F-FSPG is specifically taken up via the system xC- 
transporter, a glutamate-cystine exchanger (SLC7A11/SLC3A2 heterodimer) that transports 
amino acids L-glutamate and L-cystine (Cys-S-S-Cys) into the cell. The release of highly abundant 
intracellular glutamate is the driving force for efficient uptake of cystine and 18F-FSPG. Isotopic 
dilution of 18F-FSPG in a large intracellular glutamate pool leads to efficient trapping of the tracer, 
with no further metabolism of the tracer observed. Intracellularly, cystine is rapidly reduced to 
two molecules of cysteine (Cys-SH) and represents the rate-limiting precursor for glutathione (27) 
biosynthesis. Redox maintenance and a constant supply of GSH are especially important in tumor 
cells as protection against reactive oxygen species (ROS) and for tumor survival (28). As a result, 
many tumor cells possess a survival advantage over normal cells because they express a higher 
expression of the xC- transporter, accumulate higher levels of L-cysteine and L-glutamate, and thus 
maintain high levels of GSH to detoxify ROS efficiently (29). 
 
In contrast to the modified intermediary metabolism often found in tumors, infection and 
inflammation related processes are primarily dominated by a high rate of glycolysis and/or 
glutaminolysis. Infiltrating macrophages and most other inflammatory cells do not proliferate at 
the target site, and thus depend mainly on glucose or glutamine to meet their bioenergetic 
requirements. ROS and redox-balancing processes are also important in these settings, wherein 
system xC- may also play a role. However, the absence of an intracellular glutamate pool should 
 
Figure 1. Biological rationale for PET imaging 
of tumor cell metabolism. Role of glutamate 
(top) in tumor cell metabolism. 


THO 1524: [18F]FSPG PET Protocol 
 
 
 
 
 
 
 
Protocol Date: 10/03/2019 
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not lead to high transporter activity and/or tracer retention as observed in tumor cells. This needs 
to be investigated in more detail and will be also part of this study to gain further insight for future 
applications of 18F-FSPG as a targeted cancer-imaging agent in the clinic. 
 
Preclinical PET imaging studies with 18F-FSPG indicated superior tumor imaging when compared 
with 18F-FDG with rapid clearance from the blood and whole body leading to a low background 
from healthy organs and tissues. For example, a high uptake and retention of 18F-FSPG in NCI-
H460 lung cancer cells was observed in vitro and in vivo. Other lung tumor cells lines (A549, NCI-
H322, NCI-292) were studied with similar results (26). 
 
Furthermore, 
18F-FSPG was tested in several inflammation models. In a combined 
tumor/inflammation model, where inflammation was induced by turpentine oil, 18F-FSPG showed 
superior differentiation of tumor tissue from inflammatory lesions compared to 18F-FDG (26). 
Other inflammation models were studied but the results are not yet published (personal 
communication Piramal Imaging). This included also inflammation models using Freund’s 
complete adjuvant, a colitis model, and a wound healing/scar tissue model that showed similar 
results to the turpentine oil model and were all negative for 18F-FSPG uptake. Only a rodent model 
of lymphadenitis and one mouse with incidental histiocytosis were observed to be positive for 
FSPG. More research is needed to understand what led to increased 18F-FSPG uptake and 
retention in this situation, though sarcoidosis and active tuberculosis do demonstrate strong 18F-
FSPG uptake(30). 
 
Toxicology and safety pharmacology studies with the 19F-labeled drug substance (“cold” fraction 
of the active compound) and decayed drug formulation (containing by-products and impurities) 
confirmed that 18F-FSPG can be used in clinical trials. Furthermore, the calculated effective 
radiation dose (ED) dose is within acceptable limits for PET imaging in humans (see below).  
 
In a pilot clinical study of lung and breast cancer by Baek et al. (31) a high tumor detection rate 
was observed for NSCLC but not for breast cancer. A positive 18F-FDG-PET was used as the 
inclusion criterion. All 10 18F-FDG-positive lung cancer patients showed 18F-FSPG uptake. 
Interestingly, Baek et al. reported that elevated glycolytic activity and uptake of 18F-FSPG 
appeared to be correlated in lung cancer, while a similar relationship was not observed in breast 
cancer (31). Immunohistochemical (IHC) analyses on these subjects’ pathology samples showed 
significant correlation between 18F-FSPG uptake and protein expression of both the SLC7A11 
subunit of system xC- and the stem cell marker CD44. In breast tumor samples specifically, IHC 
showed that absence of CD44 correlated with low signal from 18F-FSPG-PET, even if the SLC7A11 
subunit was present, indicating possible importance of CD44 co-expression for system xC- 
function. The standardized uptake values of 18F-FSPG for non-small cell lung cancer (NSCLC) 
averaged 7.6 (+/- 7.3), versus 13.0 (+/- 6.7) for 18F-FDG. While the average uptake values for 18F-
FSPG were lower than for 18F-FDG, Baek, et al, (31) demonstrated that the background signal was 
lower for 18F-FSPG, leading to comparable tumor to background ratios with 18F-FDG. 
 
In a pilot clinical study 18F-FSPG PET was investigated in patients with inflammatory lesions and 
compared with 18F-FDG. The SUVmax of all lesions was significantly lower (~3.6 times) for 18F-FSPG 
compared to 18F-FDG (SUVmaxFSPG: 1.8 versus SUVmaxFDG: 6.5), with the exception of sarcoid lesions; 
rapid washout was also observed. Such incidences in our target population is low and it is 
expected that these are unlikely confounders on the differential diagnosis. 


THO 1524: [18F]FSPG PET Protocol 
 
 
 
 
 
 
 
Protocol Date: 10/03/2019 
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The SUVs for 18F-FSPG in NSCLC were higher compared with other radiopharmaceuticals in this 
setting: 18F-Fluorothymidine (18F-FLT) showed SUV values of 3.54 (+/- 1.98) (32). Hustinx et al. (33) 
reported on the use of another amino acid (2-18F-fluoro-L-tyrosine, 18F-TYR) for imaging in cancer, 
including lung cancer, but with only 6 out of 11 lung cancer patients demonstrating similar staging 
compared to 18F-FDG, with the 18F-TYR SUV value for lung cancer being approximately 2.0. Beer 
et al. (34) investigated a PET imaging probe for angiogenesis, 18F-galacto-RGD, and compared it to 
18F-FDG in PET/CT imaging of 18 patients with primary or metastatic cancer, 10 of whom had 
NSCLC, with analysis of uptake in all primary tumor and metastatic lesions. There was no 
correlation between the uptake values of 18F-galacto-RGD and 18F-FDG, with the latter probe being 
clearly superior. Thus, while radiolabeled amino acids have proven limited usefulness for PET 
imaging of neoplasms in the lung, prior attempts to use amino acids and other PET imaging agents 
beyond 18F-FDG are, until now, of limited clinical value. 
 
In summary, 18F-FSPG is a novel PET tracer to assess the activity of system xC- and has shown 
promise as a cancer-imaging probe in a variety of preclinical and clinical settings. A favorable 
biodistribution pattern and a high lesion detection rate previously seen in rodents (26) was 
confirmed in patients with different tumor types. Phase I clinical trials have been completed 
assessing the safety and tolerability as well as the tumor targeting potential and tumor 
accumulation of 18F-FSPG in healthy volunteers and patients with various cancers. To date, 18F-
FSPG has been evaluated in patients with breast and lung cancer, where the tracer exhibited a 
promising detection rate of tumors with xC- transporter activity (31). Ten of 10 18F-FDG-positive 
lung cancer patients showed 18F-FSPG uptake. Interestingly, Baek et al. reported that elevated 
glycolytic activity and uptake of 18F-FSPG appeared to be correlated in lung cancer, but a similar 
relationship was not observed in breast cancer (31).  
 
Benefit of this research to patients 
 
This research may impact patient care in a number of positive ways. Results from this study have 
the potential to establish a new role for non-invasive molecular imaging in distinguishing benign 
indeterminate pulmonary nodules from lung cancer. The benefits potentially include reducing the 
need for some follow-up CTs, unnecessary invasive biopsies with attendant morbidity and rare 
mortality, reducing patient anxiety, and an overall decrease in wasted healthcare spending. If 18F-
FSPG PET is shown to be more specific for lung cancer compared to 18F-FDG PET for diagnosis of 
IPNs, 18F-FSPG PET may enable improved detection of smaller lesions and improved discrimination 
of benign from malignant lesions compared to the current standard of care assessments. 
 
2. Objectives, Rationale, and Specific Aims 
 
This is a hypotheses-driven prospective clinical trial of an emerging, molecularly targeted PET 
reagent, 18F-FSPG. 
 
The objective is to test the hypothesis that 18F-FSPG PET/CT will provide improved accuracy in 
diagnosis of IPNs compared to the current PET/CT imaging standard-of-care with 18F-FDG. 
 
Our rationale is that 18F-FSPG PET/CT may yield improvements in discrimination of tumor from 
benign IPNs. 


THO 1524: [18F]FSPG PET Protocol 
 
 
 
 
 
 
 
Protocol Date: 10/03/2019 
9 
 
There are three Aims: 
 
Specific Aim 1: To compare the imaging characteristics of 18F-FSPG PET/CT with standard-
of-care, 18F-FDG PET/CT.  
 
Hypotheses: 18F-FSPG will accumulate in lung tumors with equal or improved sensitivity and 
increased specificity over SOC 18F-FDG PET/CT.  
 
Approach: We will determine and compare the accuracy in discrimination between benign and 
malignant lung nodules detected by CT between these two 18F imaging probes for the 
diagnosis of lung cancer in a population whose IPN’s are 7-30 mm in maximum diameter, or 
in lung masses not yet biopsied that are more than 3 cm in diameter.  
 
Specific Aim 2: To compare the imaging characteristics of 18F-FSPG PET/CT to standard-of-
care 18F-FDG PET/CT in patients with newly diagnosed lung cancer. 
 
Hypotheses: 18F-FSPG will provide improved baseline diagnosis and staging of lung cancer 
relative to SOC PET/CT using 18F-FDG.  
 
Approach: We will determine whether 18F-FSPG PET/CT is superior to 18F-FDG PET/CT for 
baseline diagnosis and staging of lung cancer, and whether the biodistribution of 18F-FSPG 
varies in various histological subtypes, grades, and stages of lung cancer.  
 
Specific Aim 3: To determine whether 18F-FSPG uptake in lung cancer can be predicted based 
on correlation with CD44 and xC- expression in surgical pathology specimens. 
 
Hypotheses: 18F-FSPG PET will correlate with xC- and CD44 immunoreactivity in tumor and non-
tumor (IPN) tissues.  
 
Approach: Core or surgical biopsies and/or autopsy specimens will be obtained from, following 
standard-of-care for subjects, in Specific Aims 1 or 2. This profiling will allow us to determine 
whether FSPG uptake may potentially distinguish a subclass of lung cancers with different 
clinical behavior, e.g. possibly identifying very high risk disease even in early stage lung cancer.  
 
3. Animal Studies and Previous Human Experience 
 
Published reports note that 18F-FSPG has been evaluated previously in rodents and humans (31, 
35-37) . To date, 18F-FSPG has been evaluated with promising results in over 70 patients with 
lymphoma and lung, breast, head and neck, brain, and prostate cancers, where the tracer 
exhibited a promising detection rate of tumors with xC- transporter activity. In a pilot study 
conducted at Seoul, South Korea, Baek et al. reported that elevated glycolytic activity and uptake 
of 18F-FSPG appeared to be correlated in lung cancer, but a similar relationship was not observed 
in breast cancer (31). In preclinical studies, 18F-FSPG exhibited greater tumor avidity compared to 
inflammation in a combined tumor-inflammation model in rats (26). In another publication from 
Korea, 18F-FSPG was evaluated to be useful in patients with HCC who exhibited a range of 18F-FDG 


THO 1524: [18F]FSPG PET Protocol 
 
 
 
 
 
 
 
Protocol Date: 10/03/2019 
10 
PET results (35). To date, in human studies, 18F-FSPG PET has been well tolerated, with no reported 
safety concerns (35).  
 
4. Patient Eligibility & Inclusion / Exclusion Criteria 
 
Participants will be recruited by Vanderbilt University Medical Center and Tennessee Valley 
Health System Nashville (TVHS) study team members. Patient history will be reviewed for 
inclusion/exclusion criteria and informed consent obtained as described below. 
 
Enrollment will be open to all patients of both genders with the above diagnoses described in the 
Specific Aims, with the following inclusion/exclusion criteria. 
 
A. Inclusion Criteria 
 
1. Adult patient (age 40 - 80). 
2. An indeterminate pulmonary nodule (IPN) (7–30 mm diameter) on CT, or an indeterminate 
lung mass (> 30 mm diameter), without prior examinations that establish that the lesion has 
been stable for two or more years.  
3. Untreated. 
 
OR 
4. An adult patient with a newly diagnosed, untreated primary lung cancer diameter 7 mm or 
more.  
 
AND 
5. The patient must provide informed written consent, which will include a layman’s explanation 
of the estimated amount of additional radiation that the patient will receive from the 
investigational PET/CT scan using 18F-FSPG. 
 
6. The patient must agree at the time of study entry to undergo clinically indicated biopsy(ies) or 
a 24-month period of follow-up, as needed, to resolve the etiology of their IPN(s) or lung mass(es).  
 
 
B. Exclusion Criteria 
 
1. Pregnant or lactating patients will be excluded, as will females of childbearing potential who 
refuse to undergo a serum or urinary beta-HCG pregnancy test the day of either the 18F-FSPG 
or the 18F-FDG PET/CT scans, in accordance with the standard policy of the Medical Imaging 
Service at our facility. Women who have experienced 24 consecutive months of amenorrhea, 
have reached at least 60 years of age, or have had a tubal ligation or hysterectomy 
documented in their medical records are considered not to be of childbearing potential for 
the purposes of this protocol.  
 
2. Patients with a body weight of 400 pounds or more or a body habitus or disability that will 
not permit the imaging protocol to be performed, due to the compromise in image quality on 
both CT and PET/CT.  If the standard-of-care 18F-FDG/PET was of diagnostic quality as 
determined by the official clinical interpretation, then this will be presumptive evidence that 


THO 1524: [18F]FSPG PET Protocol 
 
 
 
 
 
 
 
Protocol Date: 10/03/2019 
11 
the patient’s body habitus and/or disabilities should not prevent a diagnostic quality 18F-FSPG 
PET/CT scan, either. 
 
3. A recognized active lung infection (this will confound the standard-of-care 18F-FDG PET/CT 
scan). 
 
4. Previous systemic or radiation treatment for cancer of any type within 1 year. 
 
5. For patients who do not have a tissue diagnosis:  
A. 
Non-oncologic severe co-morbidities suggesting a life span of less than two years 
if not treated, as determined by the potential subject’s treating physician.  
B. 
If severe co-morbidities are present, the treating physician should indicate that a 
life span of 2 years is expected if treatments are effective.  
C. 
This exclusion is to prevent loss of the needed 2 year CT follow-up to establish a 
benign diagnosis for lesions lacking tissue diagnosis if extremely fragile subjects 
are enrolled and then experience an untimely, unrelated death.  
 
5. Enrollment/Randomization  
 
We propose a three (3) year funded prospective cohort with consecutive subject 
enrollment throughout each year. We will enroll subjects referred to the Oncology, Thoracic 
Surgery or Pulmonary Medicine Services at Vanderbilt University Medical Center and Tennessee 
Valley Healthcare System Nashville. We will allow a 2-year follow-up of all subjects to document 
stability by CT for IPNs that do not have a tissue diagnosis (stability on CT for two years of an IPN 
or mass is accepted presumptive evidence of benignity). Follow-up will be from the day of the 
baseline CT, and may be extended later if needed. At VUMC, we see about 750 patients with newly 
diagnosed IPNs annually, and about 400 patients with newly diagnosed lung cancer. Accordingly, 
given the high prevalence of granulomatous IPNs in our geographic region, we are well suited to 
perform the work we have described.  
 
We will perform an analysis to correlate the 18F-FSPG PET/CT findings with 18F-FDG PET/CT 
and the surgical pathology results for the patients who have tissue correlation. Each subject will 
receive the “standard-of-care” 18F-FDG PET/CT as indicated for patients at high risk for lung cancer 
who have an IPN or lung mass meeting our size criteria, and will also receive the investigational 
18F-FSPG PET/CT, with no intervening treatment of the target lesion(s). After enrolling 30 subjects, 
we will close enrollment but continue the study for data collection and analysis until the funding 
period ends and/or sufficient follow-up for diagnosis (up to 2 years) has occurred, and report our 
results in the peer-reviewed literature. 
 
Should we achieve clear statistical superiority of 18F-FSPG PET/CT over 18F-FDG PET/CT 
before that time, we will pursue a larger trial to offer improved benefit of our patients for the 
diagnosis of IPNs and/or staging of lung cancer (see Go/No-Go criteria in Study Design). While 2 
years’ stability in nodule size is the “gold standard” for CT, well over 90% of cancers demonstrate 
growth on CT within one year. We will also perform the research outlined in Specific Aim 3 on 
tissue specimens obtained from our subjects in Specific Aims 1 and 2. If we find significant added 
value from the use of 18F-FSPG in either IPNs or lung cancer, we will propose further investigations. 
Final diagnosis will be based on tissue biopsy (surgical or via a high-quality core biopsy) 
or negative (no growth) two-year follow-up with CT. We will assign patients with IPNs into the 


THO 1524: [18F]FSPG PET Protocol 
 
 
 
 
 
 
 
Protocol Date: 10/03/2019 
12 
“benign” category if their IPNs remain stable for two or more years, decrease in size, or resolve 
during CT follow-up, performed in accordance with Fleischner Society guidelines.  
 
Patient Registration 
 
All patients MUST be registered with the Vanderbilt-Ingram Cancer Center (VICC) prior to the start 
of research procedures for all sites.   
 
Patients will be centrally registered with the Vanderbilt-Ingram Cancer Center (VICC) at study 
entry by emailing the Multi-Institutional Team at coordinating.center@vumc.org. At the time of 
registration, the following documents must be submitted:  
 
• 
Copy of the patient’s signed and dated Informed Consent 
• 
Patient Enrollment From  
• 
Eligibility Checklist including source documents to verify eligibility 
 
The VICC Coordinating Center will assign sequence numbers to all patients in screening. Sequence 
numbers will not be re-used if a patient screen fails.  
 
6. Data Management and Monitoring 
  
Participating institutions will be collaborating with Vanderbilt in patient accrual. Data will be 
collected using a centralized electronic case report form called ON-line Clinical Oncology 
Research Environment = Oncore (http://www.vicc.org/ct/research/oncore.php). Oncore is a 
highly secure, web based, cancer specific, and customizable system that provides fully 
integrative clinical data management and study administration capabilities developed in an 
ongoing collaborative effort with NCI designated Comprehensive Cancer Centers.  It fully 
integrates study administration functionality including protocol tracking, patient registration, 
NCI reporting, review committee tracking, and SAE tracking, with clinical data management 
functionality including electronic case report forms (eCRF) design, clinical data capture, protocol 
and regulatory compliance monitoring.  Also the system is capable in storing basic protocol 
information (e.g., IRB approval dates, dates for annual renewals,) and clinical trials research 
data.  Oncore allows the investigator to define specific protocol requirements and generate data 
collection forms.  Creation of the data collection form is done with a single button click after the 
parameters of an individual protocol have been specified. Oncore permits specification of study 
protocols, management of patient enrollment, clinical data entry and viewing, and the 
generation of patient or study-specific reports based on time stamping.  OnCore is embedded 
with a comprehensive domain repository of standard reference codes and forms to promote 
standardization. The sources for the repository include CDUS, CTC, CDEs from NCI, ICD, MedDRA 
and various best practices from contributing NCI-designated Comprehensive Cancer Centers. 
OnCore provides several reporting features specifically addressing NCI Summary 3 and Summary 
4 and other reporting requirements. Data may also be exported in a format suitable for import 
into other database, spreadsheets or analysis systems (such as SPSS). This system will be used to 
manage all VICCC clinical trials data. OnCore is maintained and supported in the VICC Clinical 
and Research Informatics Resource.  
 


THO 1524: [18F]FSPG PET Protocol 
 
 
 
 
 
 
 
Protocol Date: 10/03/2019 
13 
Specified members at each participating site will submit all pertinent regulatory documents to 
the Coordinating Center, who will store it in a secure location.  
 
As the Coordinating Center, Vanderbilt has responsibilities to health authorities to take all 
reasonable steps to ensure the proper conduct of the study as regards to ethics, protocol 
adherence, integrity, validity of the data recorded on the CRFs, and adherence to regulations 
regarding Good Clinical Practice (GCP) and the protection of human subjects. 
 
In accordance with applicable regulations, GCP, and Coordinating Center procedures, sites will 
be contacted prior to the start of the study to review with the site staff the protocol, study 
requirements, and their responsibilities to satisfy regulatory, ethical, and Coordinating Center 
requirements.  
 
During the course of the study, the Coordinating Center will routinely monitor sites for protocol 
compliance, compare CRFs with individual subjects’ original source documents, assess drug 
accountability, and ensure that the study is being conducted according to the pertinent 
regulatory requirements. The review of subjects’ medical records will be performed in a manner 
to ensure that subjects’ confidentiality is maintained. Monitoring visits will primarily be 
conducted remotely, and sites are required to provide the appropriate source documentation in 
order to allow for proper oversight per GCP. Investigators must agree to cooperate with the 
Coordinating Center to ensure that any problems detected are resolved. 
 
The VICC DSMC meets on a quarterly basis and ad hoc to discuss data and safety monitoring of 
clinical trials and to oversee the VICC DSMP. Internal audits for compliance with adverse event 
reporting, regulatory and study requirements, and data accuracy and completion are conducted 
according to the VICC DSMP according to study phase and risk. The committee reviews all 
serious adverse events (SAE) on Vanderbilt sponsored investigator-initiated studies on a 
quarterly basis and provides DSMC SAE review reports to the Vanderbilt IRB. 
 
7. Study Procedures & Data Collection 
 
Baseline Imaging: CT 
 
 
Each patient will have a diagnostic CT within 180 days prior to enrollment (as part of the 
standard of care) to define the pathologic conditions necessary to be enrolled, and be untreated 
for the IPN or lung cancer for which the patient is being evaluated. These prior scans must be 
immediately available to the investigators for review. Outside CT scans found to be of good quality 
will be acceptable if they are available in native (uncompressed) DICOM format.  
 
Imaging Protocol: 18F-FSPG (Figure 1) 
 
 
Each patient will undergo an SOC whole-body (vertex to mid thighs) 18F-FDG PET/CT scan 
within 60 working days of an 18F-FSPG PET/CT scan for these first 60 enrollees, with no intervening 
cancer treatment of the target lesion (limited biopsies or resections are allowed). A minimum of 
12 hours must lapse between SOC (18F-FDG) and 18F-FSPG PET/CT scans. Standard of care 
procedures performed prior to consent but within the protocol defined windows for each 


THO 1524: [18F]FSPG PET Protocol 
 
 
 
 
 
 
 
Protocol Date: 10/03/2019 
14 
assessment can be used for study purposes. All research only procedures must be performed after 
the consent date. 
 
Eight (8) subjects with either indeterminate nodule(s) or thought or known to have newly 
diagnosed lung cancer, will receive an 18F-FSPG PET scan (emission only), acquired dynamically 
after injection over the nodule/mass of interest for 60 minutes, in order to characterize the time 
activity curves of 18F-FSPG. These 8 subjects will then have a short break (bathroom, stand up) 
and then receive a PET/CT scan from the vertex to the mid-thighs.  This final body PET/CT covers 
the same anatomic range as the SOC 18F-FDG PET/CT, and will be compared closely to the 18F-FDG 
PET/CT to determine if there is added value of the 18F-FSPG PET/CT.  Once the dynamic PET/CT 
scans with 18F-FSPG in the initial 8 subjects are obtained, the remainder of subjects will have a 
scanning protocol from vertex to mid-thighs about 60 minutes after 18F-FSPG injection, similar to 
the protocol for standard of care 18F-FDG PET/CT. 
 
The third year will be used, if needed, to obtain at least two years of CT follow-up for 
patients with IPNs who chose serial follow-up CT scans over a tissue diagnosis (two years is 
required by Fleischner Society Guidelines to prove stability/benignity for solid nodules), though 
over 90% of malignant IPNs will demonstrate growth within one year by CT. 
 
Figure 1:  Flow Schema of Imaging: 
 
  
*Optional tissues collection noted in Figure 1 are part of separately enrolled study and not called 
for on this protocol.  
 


THO 1524: [
18F]FSPG PET Protocol 
 
 
 
 
 
 
 
Protocol Date: 10/03/2019 
15 
 
It is possible that we will complete enrollment of sufficient patient numbers prior to the 
end 
of 
year 
1, 
in 
which 
case 
we 
will 
continue 
the 
clinical 
follow-up 
period 
for 
the 
remainder 
of 
the 
proposed investigational period until the end of the proposed funding or until (if sooner) we 
achieve clear statistical advantage of 
18F-FSPG over 
18F-FDG PET/CT for the diagnosis of IPNs 
and/or staging of lung cancer. If statistical superiority of 
18F-FSPG PETCT is established, we will 
initiate a larger 
trial (additional 40 subjects) for the use of 
18F-FSPG PET/CT in the 
diagnosis if IPNs 
(Specific Aim 1) and/or evaluation of lung cancer (Specific Aims 2 and 3) (see Go/No-Go criteria in 
Study Design). 
 
At Vanderbilt University Medical Center, the human PET scanners are integrated PET-CT 
systems. Therefore,  a whole body transmission CT scan without contrast is performed on all 
patients who undergo a PET scan. The transmission CT scan is used to correct the PET images for 
attenuation and provide CT images for anatomical mapping. The 
18F-FSPG will be prepared by the 
Vanderbilt University Medical Center Radiochemistry Core Laboratory under IND 124202 (H. 
Charles Manning, PI). For consistency, patients will fast at least four (4) hours and the blood 
glucose concentration (“finger-stick” in the PET area) will be determined prior to injection of all 
radiopharmaceuticals. 
 
Analysis of 
18F-FDG and 
18F-FSPG PET/CT images will be performed independently by at 
least 2 physicians at VUMC who are experienced in PET/CT interpretation with a third physician 
used for consensus if there is a disagreement as to interpretation. The images will be interpreted 
with US FDA software on VUMC’s GE Healthcare AW 2 and/or Xeleris 3 workstations. 
  
Radiotracer Production  
 
 
18F-FSPG 
is 
obtained 
by 
radiolabeling 
of 
the 
protected 
precursor 
di-tert-butyl 
(2S,4S)-2-(3-
((naphthalen-2-ylsulfonyl)oxy)propyl)-4-(tritylamino)pentane-dioate) (PI-021) with  [
18F]fluoride. 
After acidic deprotection, the tracer is purified over cartridges and finally formulated for i.v. 
injection 
by 
passing 
the 
solution 
through a 
0.22-m sterile 
filter. 
It 
has a 
half-life 
of 
109.7 
minutes. 
The synthesis is performed 
within an automated synthesis module in a lead-shielded hot cell. The 
production methods, sterile filtration, and formulation are all carried out under Vanderbilt-held 
IND  124202, and allow for the production of  a sterile and pyrogen-free solution ready for 
injection. 
 
18F-FSPG PET Procedure and Dynamic Data Analysis 
 
 
For 
18F-FSPG and standard of care 
18F-FDG PET/CT, imaging is described above.  The 
dynamic analysis of the first 60 minutes of emission-only imaging will be analyzed as described 
below, in the initial 8 subjects, and used to determine the optimal imaging protocol, via analysis 
of 
time 
activity 
curves, 
for 
the 
investigational 
radiopharmaceutical 
to 
evaluate 
indeterminate 
lung 
nodules and lung cancer.  This analysis 
will be performed at the Vanderbilt 
University Institute for 
Imaging Sciences (VUIIS), Manning laboratory, on dedicated workstations with appropriate 
software tools in place. 
 
Clinical Data Analysis 
 
 
The research PET/CT studies will be interpreted independently by two experienced 
nuclear medicine (NM) physicians blinded to each other’s interpretation. These NM physicians 
will render 
“un-blinded” interpretations with access to 
conventional imaging studies and all 
other 


THO 1524: [18F]FSPG PET Protocol 
 
 
 
 
 
 
 
Protocol Date: 10/03/2019 
16 
relevant information available in the patients’ medical records. The final PET/CT interpretations 
(18F-FSPG; 18F-FDG PET/CT, clinical CTs and other relevant clinical imaging available for 
comparison) will then be compared to determine the impact of 18F-FSPG PET/CT on the final 
diagnosis, and specifically to determine if the 18F-FSPG PET/CT would have changed the diagnosis 
and/or stage of disease compared to the clinical SOC CT and/or 18F-FDG PET/CT.  These results will 
be reported to the biostatistician who will compile the data for estimation for analysis (see 
Statistical Consideration Section).   
 
At this time, the investigational data will not be used to direct care (e.g. influence treatment 
decisions) until we have sufficient knowledge of the usefulness of the data in this regard 
compared to standard of care procedures. 
 
Rationale for Size Criteria 
 
 
The rationale of a minimum diameter of 7 mm for IPNs and lung cancer for our 
investigation is based on the usual lower limit of detectability on PET imaging. While this is usually 
reported as 8-10 mm in the literature, much of this is based on older technology PET scanners. 
The size of 7 mm is also the minimum size in which evaluation of an IPN becomes technically 
feasible (11, 38) in terms of: 
 
1) Number of patients to manage 
2) Limited clinical means by which to obtain tissue diagnosis of such a small IPN 
3) Risks/benefits of definitive evaluation of a nodule this small 
 
While overall very safe, definitive evaluation of such small IPNs often requires a core biopsy via 
a transthoracic or transbronchoscopic biopsy, VATS wedge resection or even an open 
thoracotomy since fine-needle biopsies are often non-definitive. Given the co-morbidities 
frequently present in patients at high risk for lung cancer, the perioperative mortality is likely to 
be 1.0%. Since the majority of IPNs, even in high-risk patients, are benign, we must choose a 
minimum size threshold at which the potential benefits for the patient justify the pain, cost and 
risk of a definitive answer.  
 
Henschke et al. (39) recently addressed this in a retrospective review of 21,136 subjects enrolled 
in a low-dose CT lung cancer screening program performed between 2006–2010, in which 
malignancy rates of various size ranges of IPNs were evaluated. With a cut-off of 7 mm in 
diameter for IPNs, instead of 5 mm, was used, the percentage of patients with a “positive” 
screening CT at baseline for an IPN decreased from 16% (5 mm threshold) to 7.1% (7 mm 
threshold). When these patients were then evaluated for subsequent diagnosis, a delay in 
diagnosis of lung cancer by 9 months occurred in about 5% of patients using the threshold of 7 
mm diameter as the minimum size for close interval follow-up, while the percent of “positive” 
screening exams decreased by over half (Table 1). Accordingly, though still debated, the 
definition of a “positive” CT screening examination for lung cancer will likely need to address 
practical, realistic management issues that will include the size of the IPNs to be definitively 
evaluated versus followed, particularly given the low but real morbidity/mortality associated 
with invasive procedures when the vast majority of even high-risk patients will have a benign 


THO 1524: [
18F]FSPG PET Protocol 
 
 
 
 
 
 
 
Protocol Date: 10/03/2019 
17 
IPN. Given these practical management results and the limits of resolution of current PET 
scanners, we have chosen the lower limit of size for our investigation of IPNs or lung cancer to 
be 7 mm. 
 
Table 1* 
IPN diameter (mm) defining a “positive” CT 
5 
6 
7 
8 
9 
Total percent of patients “positive” on CT 
16% 10.2% 
7.1% 
5.1% 
4.0% 
Patients (%) meeting diameter threshold with delay in 
cancer diagnosis of 9 months 
0% 
0% 
5.0% 
5.9% 
6.7% 
*Henschke et al. (39) 
 
Pathology Methods 
 
 
x
C− and CD44: To examine the correlation of accumulation of 
18F-FSPG PET with x
C− and 
CD44 in lung tumors, tissues specimens from fine-needle biopsies obtained from routine 
pathologic examinations will be obtained before or after PET/CT imaging for 
immunohistochemistry (IHC) and Western blotting (WB) studies. For patients having surgical 
excision/biopsy after 
18F-FSPG PET/CT, this tumor specimen will be used for further pathologic 
examination.  Tissue processing and IHC analysis of formalin-fixed, paraffin-embedded  tissue 
sections will be performed as detailed in our previous publications (40, 41). Briefly, 4-m thick 
whole tissue sections were transferred onto poly-L-lysine-coated adhesive slides and dried at 74 
°C for 30 minutes. After standard heat epitope retrieval for  1 hour in EDTA, pH 8.0, in the 
autostainer, the samples were incubated with antibodies for targeted epitopes. The level of 
expression of our proteins in both membrane and cytoplasm and in the membrane of malignant 
tumor cells will be examined by an experienced pathologist who is completely blinded to any 
patient and imaging information. The numerical results of the IHC will be semiqualitatively 
evaluated 
using a scale 
of 
0, 
1+ 
(weak), 
2+ 
(medium), 
and 
3+ 
(strong) 
with a 
sample 
being 
reported 
as positive if greater than 10% of the cells in the sample were positively stained. The correlation 
between the intensity of IHC staining and SUVmax of the corresponding lesion on the PET/CT will 
be assessed. 
This 
processing 
approach 
will 
allow 
for 
comparison 
of 
definite 
pathology 
and 
tracer 
imaging findings. 
 
TMAs: Tumor and benign specimens will be assembled in Tissue Microarrays (TMAs) with 
associated clinical information. All TMAs will be paraffin-embedded blocks formed from cores 
derived from multiple paraffin-embedded tissue blocks, containing hundreds of cases in a single 
accessible block, fully annotated with clinical data elements covering patient demographics, past 
medical 
history, 
smoking 
history, 
details 
about 
the 
tumor 
diagnosis, 
stage, 
histology, 
imaging, 
and 
follow-up. TMA construction begins with a detailed plan and approval by the VUMC IRB and the 
VICC Lung SPORE PTIC Tissue Utilization Committee with successful data sharing agreements and 
off-site tissue banking waivers successful in the past. Slides corresponding to the tissue blocks of 
interest 
are 
reviewed 
by 
pathologist 
(Dr. 
Eisenberg) 
director 
for 
tumor 
identification 
and 
marking, 
and the block construction (Beecher Instruments, USA) is completed. To date, we have 26 lung-
specific TMAs containing samples from approximately 750 patients with associated clinical data 
and including a variety of tumor types. 
 
Immunohistochemistry (IHC): TMA  tissue sections are evaluated for intensity and 
distribution of IHC staining. Scoring is performed by one or more pathologists, including the core 


THO 1524: [18F]FSPG PET Protocol 
 
 
 
 
 
 
 
Protocol Date: 10/03/2019 
18 
Tissue Biorepository director, Dr. Rosana Eisenberg. The scoring system routinely used for 
evaluation of IHC staining is an index based on intensity and percent tumor positivity modeled 
after methods we have used extensively in the past (40). In addition to the intensity and estimate 
of percent positive tumor cells, the cellular localization of staining is documented (nuclear, 
cytoplasmic, or membrane).  
 
8. Risks 
 
Radiopharmaceutical 
 
The radiopharmaceutical (18F-FSPG) used in this study for PET scanning has been 
evaluated in humans previously (31, 35). No adverse side effects such as anaphylactic reactions, 
allergic reactions, or mortality or morbidity have been reported to the best of our knowledge. For 
a complete safety listing of 18F-FSPG, please refer to the Investigational Brochure (IB) of Piramal-
held IND 121728. The total mass of radiopharmaceuticals administered in this study is in the sub-
pharmacological amount (<100 micrograms), and thus is expected to have no physiologic effect 
on the patient or tumor. 18F-FSPG is produced by the Vanderbilt Radiochemistry Core Laboratory 
according the CMC section of Vanderbilt-held IND 124202 (Henry Charles Manning, PhD, PI) and 
meets all USP <823> requirements for a sterile, injectable PET radiopharmaceutical.  
Injection 
 
Risks and side effects related to the IV catheter may include discomforting pain at the site 
of injection, bleeding, and bruising.  
Reproductive Risk 
 
Patients should not be pregnant while on this study because the imaging agent being 
tested contains a small amount of radioactivity. This could affect an unborn baby. Female subjects 
of childbearing potential must have a negative serum or urinary pregnancy test within 24 hours 
of the proposed investigational PET/CT scan prior to injection of the investigational 
radiopharmaceutical in accordance with the policies of the Vanderbilt University Medical Center 
IRB and Department of Radiology.  
Dose Rationale 
 
A dose of 300 MBq (8.1 mCi) for 18F-FSPG studies was chosen in accordance with a typical 
radioactive dose of 18F-FDG used for oncological diagnostics (350 MBq for an adult). This dose is 
expected to provide suitable imaging contrast of the target structures. 
 
Radiation Safety  
 
Effective radiation doses for 18F-FSPG were calculated from biodistribution studies in mice 
and were determined in five healthy volunteers. Extrapolated effective doses from mice are 5.10 
mSv for a male and 6.54 mSv for a female subject, assuming a patient dose of 300 MBq and a 
bladder-voiding interval of 45 min. In humans, an effective dose of 4.5 mSv was determined in 
healthy volunteers from an injection of 300 MBq/8.1 mCi of 18F-FSPG. 


THO 1524: [18F]FSPG PET Protocol 
 
 
 
 
 
 
 
Protocol Date: 10/03/2019 
19 
Toxicity Studies 
 
The tracer (18F-FSPG) used in the study has been evaluated in humans previously without 
incident (31, 35). The evaluation of the toxicity of FSPG included an extended single-dose toxicity 
study in rats and in dogs and the evaluation of the genotoxic potential in a gene mutation assay 
(Ames test) and an assay on clastogenic effects (micronucleus assay in vitro). For a complete 
description of 18F-FSPG toxicity, please refer to the Investigational Brochure (IB) of Piramal-held 
IND 121728. Additionally, the effects of the impurities of the anticipated clinical kit formulation 
were evaluated in an extended single dose toxicity study over three days in rats with a decayed 
kit-formulation. All toxicological studies were performed according to GLP principles. Since these 
studies were intended to evaluate the chemical toxicity of FSPG and not the potential effects of 
the radiation, the non-radioactive 19F-labeled analogue was used for toxicological testing. 
9. Reporting of Adverse Events or Unanticipated Risks to Participants or Others 
 
 
Dr(s)., Shah, Manning, and attending nuclear medicine physician(s) will monitor the study 
progress and safety of the participating patients and will monitor for serious symptoms or 
toxicities on an ongoing basis. Vanderbilt’s Clinical Trials Shared Resources department will 
undertake reporting any significant adverse events to the IRB as required, to Piramal (until Piramal 
funding ceases), and to the IND holder, Dr. Manning. Dr. Manning and the study team will meet 
regularly, based on enrollment, to review and discuss any adverse events related to this study and 
report these to the FDA as required. Patients will be asked to report to the nurse any adverse 
symptoms that occur within 30 days of the research PET studies. Serious adverse events related 
to the study drug (18F-FSPG) or the performance of the PET/CT scan will be reported within three 
working days to the IRB and FDA as required, and non-serious adverse events at the time of 
continuing review. These adverse events will be recorded in the database maintained by the 
research nurse.  
 
 
Adverse events for the purposes of this imaging trial are defined as any unexpected 
medical occurrence in a subject who receives 18F-FSPG. The event does not necessarily have to be 
causally related to the PET radiopharmaceutical to qualify as an adverse event. An adverse event 
can be any unfavorable or unintended signs, symptom or disease temporally associated with the 
injection of one of the radiopharmaceuticals, whether or not it is considered related to 18F-FSPG 
PET. Subjects will be monitored for adverse events during the actual imaging period and for up six 
half-lives following the research PET study.  Since the investigational drug, 18F-FSPG, decays to 
background in 6 half-lives, these adverse events should occur within 660 minutes (11 hours) of 
administration to be investigationally related to the drug.  Other adverse events could last longer, 
such as bruising, pain, bleeding or infection at the IV injection site.  We will attempt to contact 
the subject at least one working day after the 18F-FSPG PET/CT scan, at least 12 hours after 
injection, regarding possible AEs relating to the study.   
 
We have created a reporting form for tracking AEs related to radiopharmaceuticals given in 
“microdose” (sub-physiologic) quantity.  This form will facilitate and better reflect reporting AEs 
related to diagnosis-only investigations of sub-physiological mass quantity radiopharmaceuticals.  
This AE tracking form will be submitted as a separate document to the IRB. 


THO 1524: [18F]FSPG PET Protocol 
 
 
 
 
 
 
 
Protocol Date: 10/03/2019 
20 
Serious Adverse Events (SAE) are defined in accordance with the NCI’s CTCAE Ver. 4.0.  
 
A serious adverse events is defined as, but not limited to, events that:  
• result in death  
• are life-threatening (The patient was at risk of death at the time of the event. It does 
not refer to an event which hypothetically might have caused death if it were more 
severe)  
• requires inpatient hospitalization or prolongation of existing hospitalization  
• results in persistent or significant disability/incapacity, or in a congenital 
anomaly/birth defect  
 
All serious adverse events, regardless of causality to protocol-indicated treatment, will be 
reported to the Principal Investigator and/or the Study Coordinator at each institution, and also 
to the Coordinating Center. 
 
All serious adverse events must be reported to the Coordinating Center within 24 hours of the 
investigator becoming aware of the event. Events should be reported using the Vanderbilt 
Coordinating Center SAE Form  
as well as Form FDA 3500A (Mandatory Reporting Form for investigational agents). The FDA 
form can be found online at https://www.accessdata.fda.gov/scripts/medwatch/.  
 
Both forms must be fully completed and emailed (preferred), faxed, or scanned to: 
 
ATTN: VICC CTSR Personnel 
EMAIL: Coordinating.Center@vumc.org 
FAX: (615) 875-0040 
 
If SAE documents are faxed, the Coordinating Center must be notified via email as well. Follow-
up information must also be reported within 24 hours of receipt of the information by the 
investigator. 
 
The Coordinating Center will disseminate information regarding serious adverse events to the 
participating sites as described in FDA guidance only in the case that the event(s) is/are 
unexpected, and is/are believed to be related (i.e. possibly, probably, or definitely) to the study 
medication. The Coordinating Center will be responsible for reporting of events to the FDA and 
supporters, as appropriate. 
 
Institutional Review Board 
 
All adverse events and serious adverse events will be reported to the IRB per current institutional 
standards. If an adverse event requires modification of the informed consent, these modifications 
will be provided to the IRB with the report of the adverse event. If an adverse event requires 
modification to the study protocol, these modifications will be provided to the IRB as soon as 
possible. 
 
 
 


THO 1524: [18F]FSPG PET Protocol 
 
 
 
 
 
 
 
Protocol Date: 10/03/2019 
21 
10. Study Withdrawal / Discontinuation 
 
 
Patients will be withdrawn from the study for the following reasons: withdrawal of patient 
consent, failure to adhere to physician instructions and protocol, and if the patient’s physician 
considers withdrawal to be in a given patient’s best interest. 
 
11. Statistical Considerations 
 
Study Design 
 
As we have shown from a large review of patients referred to us for IPNs and lung masses, 
18F-FDG PET/CT has 92% sensitivity but 40% specificity for diagnosis of cancer, primarily due to 
inflammatory (especially granulomatous) lung nodules in our population. For 18F-FSPG to have a 
significant impact, we assume that the sensitivity of 18F-FSPG will be equal to 18F-FDG, but that 
the specificity of 18F-FSPG for the diagnosis of lung cancer will be 80%. Given the preliminary data 
we have shown with virtually no 18F-FSPG uptake in an active granulomatous abscess, we are very 
optimistic that our approach could succeed. 
 
 
Our preliminary proposed investigation will include 30 subjects who had both PET scans 
done FDG and FSPG of patients meeting enrollment criteria and referred from the VUMC 
Pulmonary Medicine or Thoracic Surgical Oncology services. We will include those IPNs or lung 
cancers discovered via lung cancer screening or referred for a non-screened discovered IPN or 
cancer. If our preliminary data are encouraging, we will seek additional funding to enroll more to 
achieve statistical significance. However, we predict that we will need to extend the study to a 
total of 70 subjects completing a study to achieve significance.  Our plans for the additional 
funding will be to approach the current IP holder (Piramal Life Sciences) as well as to apply for 
extra-mural funding with initial data from our initial subjects. 
 
 
Go/No-Go criteria: To verify that data collected in this pilot imaging study supports 
proceeding to a larger efficacy trial, clear Go/No-Go criteria, which will be assessed at the end of 
enrollment and data analysis, have been established for each aim, and include: 
A. Aim 1 – 18F-FSPG PET/CT has equal sensitivity to 18-FDG PET/CT, with ≥50% specificity, 
compared to the proven 40% specificity of 18F-FDG PET/CT, for the diagnosis of 
indeterminate lung nodules, in our area with high endemic rates of fungal nodules. 
B. Aim 2 – 18F-FSPG PET/CT is at least equivalent in overall accuracy to 18F-FDG PET/CT for 
staging of lung cancer. 
C. Aim 3 –18F-FSPG uptake on PET/CT imaging correlates significantly with co-expressed 
(presumed heterodimer) CD44 and Xc- expression levels in surgical pathologic specimens; 
if not, pursue other explanations for 18F-FSPG uptake. 
 
A positive result in Aim 1 would support additional clinical trials (Go), but failure to achieve either 
sufficient sensitivity or selectivity for lung cancer would contraindicate further study (No-Go) at 
the present time. 
 
 
 
 


THO 1524: [18F]FSPG PET Protocol 
 
 
 
 
 
 
 
Protocol Date: 10/03/2019 
22 
Primary Endpoints:  Results from 18F-FSPG PET/CT: 
1. Demonstrate significance accuracy in discrimination of benign from malignant 
nodules/masses equal to or greater than 
18F-FDG PET/CT, especially for 
inflammatory/infectious lung nodules, or trend toward significance should additional 
subjects be enrolled. 
2. Demonstrate equivalent or superior accuracy for staging of lung cancer compared to 18F-
FDG PET/CT, or trend towards significance should additional subjects be enrolled. 
Sample Size and Study Power 
 
Because our study population will not originate solely from a lung cancer screening trial, 
it will be “enriched” for high risk of malignancy.  Thus, the sample size calculation primarily focuses 
on the power to detect the minimum clinically important difference in the specificity of 18F-FDG 
and 18F-FSPG tests (19). Accordingly, comparing to 18F-FDG PET/CT scans, we hypothesize that use 
of the 18F-FSPG PET/CT will improve specificity for lung cancer diagnosis in our study population 
from 40% (18F-FDG) to 80% (18F-FSPG). We use McNemar’s test for paired data to evaluate the 
specificity for these two methods. We assume the proportion of the discordant pairs is 0.2 and 
0.6. A sample size of 37 benign subjects provides 80% power to detect a 40% increase in specificity 
with a two-sided type 1 error = 5%. Sixty-two subjects will be recruited to take the historic lung 
cancer prevalence of 0.4 (19) for the referral population to the pulmonary medicine or thoracic 
surgery services at VUMC for an IPN or lung mass. We will also apply a non-inferiority test to show 
that the sensitivity of 18F-FSPG is not worse than the 18F-FDG. A sample size of 25 cancer patients 
achieves 82% power at a 5% type 1 error using one-sided equivalence test when the sensitivity of 
18F-FDG is 0.9 (42) and the maximum allowable difference between 18F-FDG and 18F-FSPG is 0.2. 
Thus, we propose to enroll up to 60 subjects to allow for possible dropout such as subjects lost to 
follow-up or choosing to withdraw from the study before protocol completion. 
Data Analysis 
As part of our “go/no go” analysis as initial proof of principle, we plan to enroll 30 subjects initially 
with IPNs or newly discovered lung masses, to determine if this initial enrollment will demonstrate 
a trend toward significance in accuracy for diagnosis of IPNs or lung masses.  This will be an initial, 
“proof of principle” investigation.  If not, we will consider other imaging probes.  However, if we 
do see a trend of significance, we plan on  70 subjects to complete a study. 
We will not know at time of enrollment if the subject has a benign or malignant IPN or mass. 
Historically, we have a 40% prevalence of cancer in our referral base, which, heretofore, is not a 
“screened” population. Thus, with 70 subjects completing a study, we expect that, after tissue 
confirmation or adequate clinical follow-up to establish benignity is established, to have about 42 
subjects with benign nodules and 28 with cancer. The analysis of Specific Aim 1 will focus on the 
18F-FSPG PET/CT’s ability to discriminate up-front benign from malignant lung nodules/masses in 
all subjects. Analysis of Specific Aim 2 will then focus on analysis of known/confirmed lung 
cancers. Specific Aim 3 analysis will correlate the biomarker findings as described elsewhere in 
the Project Narrative with the findings of Specific Aims 1 and 2. 


THO 1524: [18F]FSPG PET Protocol 
 
 
 
 
 
 
 
Protocol Date: 10/03/2019 
23 
Sensitivity, specificity, overall accuracy and ROC curves will be generated and compared for both 
18F-FDG and 18F-FSPG tests. Wilcoxon rank-sum or Kruskal-Wallis tests will be applied for the group 
comparisons of immunohistochemical staining (CD44 and xC- expression levels, Specific Aim 3) 
and the biodistribution characteristics of 18F-FDG and 18F-FSPG tests (Specific Aims 1 & 2). The 
demographic information such as age, smoking status/pack-year history will be tabulated. 
Descriptive statistics, including means, standard deviations, and ranges for continuous 
parameters (uptake expressed in SUVmax, SUVmean, SUVpeak) normalized to lean body mass and 
body weight, and ratios of these uptake values to cardiac blood pool and normal lung. as well as 
percentages and frequencies for categorical parameters, will be presented.  
12. Privacy / Confidentiality 
 
 
All reasonable efforts will be made to keep patient health information private and 
confidential. To satisfy the reporting requirements of regulatory bodies and study sponsors, Dr. 
Shah and the study team will report study results as needed to the National Institutes of Health 
(NIH), US Food and Drug Administration (FDA), Vanderbilt Institutional Review Board (IRB), or 
other state and federal regulatory bodies. In reporting results for publication, all medical 
information will be de-identified in compliance with HIPPA regulations. Reasonable effort will also 
be made to keep personal information in research records private and confidential. Access to 
coded research data will be limited to key study personnel. Signed consent forms will be 
maintained in a locked file cabinet in the Vanderbilt Clinical Trials office.  
 
13. Follow-up and Record Retention 
 
 
Study results will be retained in the research record for at least six years after the study 
is completed. At that time, the research information not already in the patient’s medical record 
will be stored in a locked file cabinet in the Vanderbilt Clinical Trials office. Any research 
information in the medical record will be kept indefinitely.  
 
Following closure of the study, each participating center will maintain a copy of all site study 
records in a safe and secure location. The Coordinating Center will inform the investigator at each 
site at such time that the records may be destroyed. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


THO 1524: [18F]FSPG PET Protocol 
 
 
 
 
 
 
 
Protocol Date: 10/03/2019 
24 
Study Procedure Calendar (2-year follow-up by CT only needed for subjects without a definitive 
diagnosis of the nodule or mass by biopsy) 
 
 
 
Year 0: 
Study Initiation 
Year 1 
Year 2 
Initial Visit 
x 
 
 
Consent 
x 
 
 
Finger-stick Glucose (in 
PET/CT lab) 
x 
 
 
Blood draw (for 
pregancy test for 
female subjects of 
childbearing potential 
only) 
x 
 
 
 
Chest CT Review 
SOC 
SOC 
SOC 
18F-FSPG PET/CT 
x 
 
 
18F-FDG PET/CT 
SOC 
 
 
Adverse Event Follow-
up 
Performed day after 18F-FSPG 
scan as described 
 
 
 
  
 


THO 1524: [18F]FSPG PET Protocol 
 
 
 
 
 
 
 
Protocol Date: 10/03/2019 
25 
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