Clinical trial NCT03824535
Conditions: Cigarette Smoker Current Smoker Former Smoker Multiple Pulmonary Nodules Pulmonary Nodule
Keywords: Indeterminate lung nodule
Sponsor: Andrei Iagaru
Start date: 2019-02-04; Completion date: 2021-07-30
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well 18F-FSPG positron emission tomography (PET)/computed tomography (CT) work in diagnosing early lung cancer in patients with indeterminate lung nodules. PET imaging with an imaging agent called 18F-FDG is often used in combination with a PET/CT scanner to evaluate cancers. Giving 18F-FSPG before a PET/CT scan may work better in helping researchers diagnose early lung cancer in patients with lung nodules.

Detailed description:
PRIMARY OBJECTIVES:

I. Comparison of fluorine F 18 L-glutamate derivative BAY94-9392 (18F-FSPG) accumulation with fludeoxyglucose F-18 (18F-FDG) accumulation to assess whether (4S)-4-(3-18F-Fluoropropyl)-L-Glutamate (18F-FSPG)-PET is better at discriminating between benign and malignant nodules.

SECONDARY OBJECTIVES:

I. To develop and validate early lung cancer detection biomarkers that would directly impact the growing need to integrate imaging and non-invasive molecular diagnostics for indeterminate pulmonary nodules and allow physicians to avoid unnecessary invasive procedures in patients with benign lung disease.

OUTLINE:

Patients receive 18F-FSPG intravenously (IV) and, undergo a PET/CT scan over 30-60 minutes. Within 24 hours-14 days, patients receive 18F-FDG and undergo a second PET/CT scan over 30-60 minutes.

After completion of study, patients are followed up within 24-72 hours.

Arms: arm 1: Patients receive 18F-FSPG IV and, undergo a PET/CT scan over 30-60 minutes. Within 24 hours-14 days, patients receive 18F-FDG IV and undergo a second PET/CT scan over 30-60 minutes.
Interventions: intervention 1: Computed Tomography intervention 2: Fludeoxyglucose F-18 intervention 3: Fluorine F 18 L-glutamate Derivative BAY94-9392 intervention 4: Positron Emission Tomography (PET/CT)
Intervention descriptions: intervention 1: Undergo PET/CT intervention 2: Given IV intervention 3: Given IV intervention 4: Undergo PET/CT

Protocol documents:
Prot_SAP_001.pdf: 
IRB-46607 
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Co-Investigators 
Brian Shaller, MD 
Alice Fan, MD 
Andrei Iagaru, MD 
Biostatistician 
Jarrett Rosenberg, PhD 
Project Manager 
IRB-46607 
LUN0106 
NCT03824535 
IND 125516 
Version date:  08 June 2023 
Initial SRC Approval Date – 30 October 2018 
18F-FSPG PET/CT and Integrated Biomarkers for Early Lung Cancer Detection in Patients with Indeterminate Pulmonary 
Nodules 
18F-FSPG PET/CT and Integrated Biomarkers for Early Lung Cancer Detection in Patients with 
Indeterminate Pulmonary Nodules 
Protocol Director 
Carina Mari Aparici, MD 
300 Pasteur Dr, H2200 
Stanford, CA 94305-5281 
drmari@stanford.edu 


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TABLE OF CONTENTS 
SCHEMA ....................................................................................................................................................... 4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ........................................................................... 5 
1. 
OBJECTIVES ........................................................................................................................................ 6 
1.1. 
Primary Objective ............................................................................................................................... 6 
1.2. 
Secondary Objective .......................................................................................................................... 6 
2. 
BACKGROUND ..................................................................................................................................... 6 
2.1. 
Study Disease .................................................................................................................................... 6 
2.2. 
Imaging agent .................................................................................................................................... 6 
2.3. 
Clinicaltrials.gov ................................................................................................................................. 7 
2.4. 
Rationale ............................................................................................................................................ 7 
2.5. 
Preliminary results .............................................................................................................................. 8 
2.6. 
Study Design .................................................................................................................................... 10 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ..................................................... 11 
3.1. 
Inclusion Criteria .............................................................................................................................. 12 
3.2. 
Exclusion Criteria ............................................................................................................................. 13 
3.3. 
Informed Consent Process ............................................................................................................... 15 
3.3.1. 
Primary Completion ...................................................................................................................... 18 
3.3.2. 
Study Completion: ........................................................................................................................ 18 
4. 
IMAGING AGENT AND PROCEDURE INFORMATION ...................................................................... 18 
4.1. 
Imaging Agent and Imaging Procedure ............................................................................................ 18 
5. 
STUDY PROCEDURES ....................................................................................................................... 20 
6. 
STUDY CALENDAR ............................................................................................................................ 21 
7. 
COMPENSATION ................................................................................................................................ 21 
8. 
ADVERSE EVENTS AND REPORTING PROCEDURES .................................................................... 21 
8.1. 
Risks and Potential Adverse Events ................................................................................................. 21 
8.2. 
Adverse Event Reporting ................................................................................................................. 22 
9. 
REGULATORY CONSIDERATIONS ................................................................................................... 22 
9.1. 
Investigational New Drug Application (IND) ...................................................................................... 22 
9.2. 
Institutional Review of Protocol ........................................................................................................ 22 
9.3. 
Data Management Plan.................................................................................................................... 22 
9.4. 
Data and Safety Monitoring Plan ...................................................................................................... 22 


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10. 
MEASUREMENTS ........................................................................................................................... 23 
10.1. Primary Outcome Measure (ClinicalTrials.gov)................................................................................. 23 
10.2. Secondary Outcome Measure (ClinicalTrials.gov) ............................................................................ 23 
10.3. Measurement Methods..................................................................................................................... 23 
11. 
STATISTICAL CONSIDERATIONS .................................................................................................. 24 
11.1. Statistical Design and Data Analysis ................................................................................................ 24 
11.2. Sample Size ..................................................................................................................................... 25 
11.3. Accrual estimates ............................................................................................................................. 26 
11.4. Criteria for future studies .................................................................................................................. 26 
12. 
REFERENCES ................................................................................................................................ 27 


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18F-FSPG PET/CT and Integrated Biomarkers for Early Lung Cancer Detection in Patients with Indeterminate Pulmonary Nodules 
SCHEMA 
 
• 
All PET imaging studies and image analysis will take place at Stanford (total of 120 patients). 
• 
Nasal brushings and blood samples will also take place at Stanford according to our own protocols. Eventually these 
samples will be combined with other cohorts (total of > 900 patients) for collective analysis with our collaborators at Boston 
University. 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
 
CBC 
Complete blood count 
CI 
Confidence interval 
CRF 
Case report/Record form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMB 
Data Safety Monitoring Board 
18F 
Fluorine-18 
FDG 
Fluorodeoxyglucose 
FSPG 
(4S)-4-(3-18F-Fluoropropyl)-L-Glutamate 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
Intravenous 
LDCT 
Low dose computed tomography 
NPV 
Negative Predictive Value 
PET/CT 
Positron emission tomography – computed tomography 
PPV 
Positive Predictive Value 
ROC 
Receiver-Operative-Characteristic 
SAE 
Serious adverse event 
SUV 
Standard Uptake Value 


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1. OBJECTIVES 
1.1. 
Primary Objective 
Comparison of 18F-FSPG accumulation with 18F-FDG accumulation to assess whether 
(4S)-4-(3-18F-Fluoropropyl)-L-Glutamate (18F-FSPG) PET is better at discriminating 
between benign and malignant nodules. 
 
1.2. 
Secondary Objective 
To develop and validate early lung cancer detection biomarkers that would directly impact 
the growing need to integrate imaging and non-invasive molecular diagnostics for 
indeterminate pulmonary nodules and allow physicians to avoid unnecessary invasive 
procedures in patients with benign lung disease. We will work with collaborators at Boston 
University to develop prediction models that could identify patients with lower likelihood of 
malignancy who can be followed by CT surveillance, instead of invasive lung biopsy. 
 
2. BACKGROUND 
2.1. 
Study Disease 
Lung cancer remains the leading cause of cancer death, in large part due to our inability to 
intercept the disease process prior to its progression to an advanced state. Cancer 
interception refers to actively interrupting the cancer development process and decreasing 
the rate of clinical presentation with advanced disease. The rate-limiting steps impeding 
effective lung cancer interception are 1) a lack of understanding of the earliest targetable 
molecular events in lung carcinogenesis; 2) the challenge of developing highly sensitive and 
specific methods for early detection; and 3) the lack of markers for predicting or monitoring 
the efficacy of interception approaches. The USPSTF recommends annual screening for 
lung cancer with low-dose computed tomography (LDCT) in adults aged 55 to 80 years who 
have a 30 pack-year smoking history and currently smoke or have quit within the past 
15 years. With the LDCT screening a growing number of lung nodules is being detected. 
The nodule size range in screen-eligible individuals generally represents intermediate risk 
where there is considerable clinical uncertainty about diagnostic approach. A sensitive 
biomarker with high negative predictive value would enable physicians to avoid unnecessary 
procedures in patients with benign lung disease, avoiding substantial risks and costs. 
2.2. 
Imaging agent 
While other radiopharmaceuticals are available, 18F-fluorodeoxyglucose (18F-FDG) is still 
the primary radiotracer clinically used for the evaluation of malignancies with PET/CT. 
18F-FDG allows the non-invasive visualization of the glycolytic pathway in cells. While 
effective for many cancer types, it also has many limitations including poor uptake in certain 
cancer types, prominent background uptake in the brain, kidneys, and often the 
gastrointestinal tract, and prominent uptake in benign inflammatory or infectious processes. 
 
New insights into other metabolic pathways utilized by tumor versus normal cells have led to 
the development of a new classes of cancer diagnostics and therapeutics. Many tumor 
types are dependent on the glutaminolytic pathway. After glutamine enters the cell, 


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glutaminase converts it to glutamate, which is subsequently used in several metabolic 
pathways in the cancer cell, including as a substrate for the Krebs Cycle and for redox 
reactions. This pathway is an alternative to the better-known glycolytic pathway mentioned 
above. Some cancers that depend on glutamine as an energy source demonstrate high 
levels of glutaminase expression and a high intratumoral ratio of glutamate-to-glutamine. 
Other glutamine-dependent tumors have normal glutaminase activity but other changes that 
may result in increased glutamine utilization. Lung cancers are described to be dependent 
on the glutaminolytic pathway (1). 
(4S)-4-(3-[18F]fluoropropyl)-L-glutamate (18F-FSPG, prior alias BAY 94-9392) is a novel 
agent for PET imaging and is specifically transported into cells via system xC-. This 
exchanger binds the amino acids glutamate and cystine with similar affinity and is able to 
transport both into the cell by exchange of abundant intracellular glutamate. Intracellular 
cystine is rapidly reduced to two molecules of cysteine, which are either used in glutathione 
(GSH) biosynthesis or contribute directly to redox maintenance. The 18F-FSPG molecule, 
as a glutamate analog, is perfectly suited to provide important non-invasive information 
about tumor biology that is uniquely different from anatomic imaging such as CT or MRI and 
from 18F-FDG. 18F-FSPG has been shown to be taken up by non-small cell lung cancers 
(2). Our aim is to evaluate this imaging agent in the indeterminate lung nodule setting and 
determine if it can be used to identify early lung cancers. 
2.3. 
Clinicaltrials.gov 
This study is registered at ClinicalTrials.gov. 
2.4. 
Rationale 
There is a growing need for markers to identify the small number of malignant pulmonary 
nodules from the large number of benign nodules identified by chest CT. We propose to 
develop integrated clinical, molecular and imaging-based models for lung cancer in older 
smokers with nodules 7 to 30 mm at elevated risk for lung cancer based on lung cancer 
screening eligibility criteria. These indeterminate pulmonary nodules (IPNs) may have been 
detected in the context of screening or incidentally as part of routine practice. While a 
number of clinical risk models exist (3, 4), this nodule size range in screen-eligible 
individuals generally represents intermediate risk where there is considerable clinical 
uncertainty about diagnostic approach. A sensitive biomarker with high negative predictive 
value would enable physicians to avoid unnecessary procedures in patients with benign lung 
disease, avoiding substantial risks and costs. Our hypothesis is that we can improve current 
lung cancer detection by incorporating detailed information about nodule imaging 
characteristics and molecular data from surrogate tissues (nose and plasma) into risk 
models. The key advances over our prior and ongoing funded work are 1) detection of 
tumor-associated mutations in plasma; 2) focusing on complete sequencing-based 
characterization of the nasal transcriptome; 3) performing single-cell RNA-seq of nasal 
epithelium to identify the cellular architecture of cancer-associated expression; 
4) incorporating imaging characteristics of the nodule uncovered by advanced semantic and 
computational methods; 5) piloting study of 18F-FSPG PET tracer; and 6) incorporating each 
of these data types together with clinical data into an algorithm that can trigger appropriate 
diagnostic workup of IPN patients. 


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2.5. 
Preliminary results 
Detection of mutations in circulating tumor DNA. We have used both targeted and whole 
genome methods (5) to identify genomic alterations in the plasma of healthy individuals and 
patients with cancer. Most recently, we have used the TEC-seq approach described above 
to examine plasma specimens from 44 healthy individuals: no mutations were observed in 
the cancer driver genes analyzed in our panel. We next analyzed plasma samples from 
lung cancer (n = 64), breast cancer (n = 46), colorectal cancer (n = 42), and ovarian cancer 
patients (n = 42). These untreated patients were largely diagnosed at stage I and II. We 
found that the concentration of ctDNA in plasma from cancer patients was ~29 ng/mL, 
significantly higher than that observed in healthy individuals (n = 44; 7 ng/mL; P = 0.001). 
By TEC-seq, we detected cancer driver mutations in plasma from over half of stage I and II 
colorectal, ovarian, lung, and breast cancer patients. The affected genes and mutation 
frequencies in the lung cancer patient plasma was similar to what has previously been 
reported (Figure 1). On average, 2.1 alterations were observed in each patient with 
detectable ctDNA, with lung cancers having a higher number of alterations per case. We 
next evaluated 216 alterations in 100 patients where matched tumor tissue and blood cells 
were available. Overall, 82 of the 100 patients (82%) had at least one alteration observed in 
the circulation that was identical to that in the tumor specimen. We therefore expect that the 
fraction of cancer patients with a ctDNA-detected mutation will increase as the TEC-seq 
panel is expanded to include more cancer-associated mutations. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1. Mutation frequencies in cfDNA of lung cancer patients. The ctDNA mutational frequencies (bars) are similar to 
previously reported tumor mutation frequencies (dots) from COSMIC for 76 out of 81 genes analyzed (P > 0.05 for 76 of 81 genes, 


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Nasal epithelial gene expression differences associated with lung cancer. We have 
previously established the feasibility of detecting lung cancer via nasal epithelial gene 
expression (6) using nasal microarray data from current or former smokers undergoing 
bronchoscopy for suspect lung cancer (as part of our validation of the Percepta™ bronchial 
genomic test for lung cancer) (7, 8). We derived a 30-gene nasal biomarker that in an 
independent test set significantly improved the performance of a clinical risk model for lung 
cancer (6). This proof-of-concept nasal biomarker was developed in the clinical setting of 
bronchoscopy, potentially enriching for higher risk patients with larger lesions. The important 
next step is to build a biomarker in the clinical setting of all indeterminate lung nodules and 
to incorporate additional molecular and imaging features. 
Single cell RNA-seq of bronchial airway epithelium. To explore the value of single cell 
transcriptomics in understanding smoking-related airway injury, we performed scRNA-seq of 
~1200 cells from 6 healthy current and 6 never smokers using CEL-Seq (9). Global 
clustering using t-SNE indicates cell subsets enriched for known airway cell-type markers 
(Figure 2). Goblet cells (MUC5AC+) are significantly more abundant in current smokers, 
whereas basal (KRT5+) and club cells (SCGB1A1+) are significantly more abundant in the 
airways of never smokers. To explore lung-cancer associated airway gene expression, we 
have performed scRNA-seq on ~1200 cells from 12 patients undergoing bronchoscopy for 
suspect lung cancer. We find expression of many genes in our bronchial airway gene 
expression biomarker (7) localizes to t-SNE cell clusters, suggesting that biomarker 
performance might be enhanced by assessing specific airway cell types. 
Semantic and quantitative imaging variables for diagnostic risk of lung cancer. Dr. Aberle 
has developed logistic regression models combining clinical and semantic imaging variables 
in 11,128 CT-detected nodules from the NLST and found that semantic imaging features 
significantly improves the performance of clinical risk models of disease in cross validation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2. Single-cell RNA-seq of the normal bronchial epithelium. t-SNE clustering of single cell transcriptomes from 6 current 
and 6 never smokers. Left: Cells are colored by smoking status, with black cells from smokers and grey cells from nonsmokers. 
Right: Cells are colored by the expression levels of known cell type markers. 


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from 0.76 (95% CI: 0.74-0.79) to 0.89 (95% CI: 0.87-0.90). In separate work, Dr. Aberle 
has identified quantitative imaging features in 146 ever smokers aged 50 to 80 years with 
incidentally-detected nodules from the UCLA EMR with high prediction performance 
(AUC-.86) in cross validation. Our preliminary data establishes the potential of both 
semantic and quantitative feature-based models for lung cancer. 
 
18F-FSPG PET tracer. Hijacking energy metabolism is a hallmark of cancer (10). 18F-FSPG 
is a glutamate analogue tracer that is transported into cells via the system xC– transporter, 
which maintains the cellular redox environment (11). This transporter is also important in 
tumor growth, progression and treatment resistance (12, 13). 18F-FSPG visualizes distinct 
tumor biology compared to 18F-FDG, which measures cellular glucose uptake (14). Studies 
at Stanford have shown that lung cancer is well visualized by 18F-FSPG with low 
background uptake (2, 15). New data suggest that 18F-FSPG has lower uptake in many 
inflammatory conditions (16), which can severely limit 18F-FDG PET accuracy (Table 1). 
We therefore hypothesize here that 18F-FSPG is a superior tracer to assess the likelihood of 
cancer in pulmonary nodules. 
Relevance of preliminary data: The preliminary data above establishes 1) our ability to 
measure a panel of mutations in ctDNA in early stage lung cancer, setting the stage for 
evaluating the panel as an early detection tool in the IPN setting; 2) nasal gene-expression 
as a potential diagnostic for lung cancer; 3) our ability to perform scRNA-seq of airway 
epithelial brushings in order to characterize the heterogeneity of the field; 4) semantic and 
quantitative imaging markers as diagnostic in the IPN setting; 5) the potential for novel 
molecular imaging markers to improve upon existing PET markers. 
2.6. 
Study Design 
120 patients with indeterminate lung nodules will be enrolled in the study at Stanford. Blood 
and nasal brushings will be collected once. The samples from these 120 patients will be part 
of a bigger cohort of over 900 patients for collaborative data analysis. 
All samples will be de-identified before shipment or other data sharing with collaborators 
takes place. An additional 70 patients who may or may not have smoking history will be 
imaged at Stanford and analyzed with the other 50 patients enrolled at Stanford. 
All 120 patients will be imaged once by 18F-FSPG PET/CT as part of this open-label, 
nonrandomized, single-dose explorative study and once by 18F-FDG PET/CT. PET/CT 
imaging will be scheduled > 24 hours apart to allow for imaging agent washout, and not 
more than two weeks apart to allow for optimal image comparison. 
Clinical diagnosis (cancer / benign disease) is based on 1) histopathology of biopsy/surgical 
specimen or 2) surveillance by CT scans for a period of 2 years to confirm that there is no 
 
 
 
 
Table 1. SUVmax with standard deviation for non-malignant lung 


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growth of the nodule. All patients without histopathological diagnosis will undergo CT 
surveillance for a 2-year period by clinical standards. 
3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
Inclusion and Exclusion Criteria are provided on the Eligibility Checklist, following, and which 
may be extracted for use in screening potential subjects. 
The following Participant Eligibility Checklist will be completed in its entirety for each subject 
prior to registration. The completed, signed, and dated checklist will be retained in the 
subject’s study file, and the study’s Regulatory Binder. 
Pursuant to Stanford Medicine SOP “Confirmation of Participant Eligibility in Clinical Trials,” 
the treating Physician (investigator); the Study Coordinator; and an Independent Reviewer 
will verify that the subject’s eligibility is accurate; complete;  and legible in source records. 
A description of the eligibility verification process will be included in the EPIC or other 
Electronic Medical Record progress note. 
 
 


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3.1. Participant Eligibility Checklists 
For each prospective study participant that is screened, the appropriate checklist will be printed, 
the results recorded, and filed in the respective subject binder or file. It is anticipated that not all 
prospective study participants will be enrolled. 
Eligibility Checklist (Group 1: Subjects with smoking history) 
I. 
Protocol Information 
 
Protocol Title: 18F-FSPG PET/CT and Integrated Biomarkers for Early Lung Cancer 
Detection in Patients with Indeterminate Pulmonary Nodules 
Group Group 1: Subjects with smoking history 
eProtocol number: 
OnCore number: 
IRB-46607 
LUN0106 
Principal 
Investigator: Carina Mari Aparici, MD 
 
II. 
Subject Information 
 
Subject name / Unique ID: 
/ 
Gender 
Male 
Female 
 
III.  
Study Information 
Inclusion Criteria 
Prospective Participant Must MATCH 
ALL these Inclusion Criteria to be Eligible 
Yes 
No 
Supporting 
Documentation * 
1. Pulmonary nodule between the size of 7 to 30 mm. 
Subjects with multiple nodules may be eligible if the 
dominant nodule is 7 to 30 mm. 
 
 
2. ≥ 45 years old 
 
 
3. Current or former cigarette smoker, with 
≥ 20 pack years 
 
 
4. Documented informed consent 
 
 


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Exclusion Criteria 
 
Prospective Participants Must NOT Match 
ANY of These Exclusion Criteria 
Yes 
No 
Supporting 
Documentation * 
1. History or previous diagnosis of lung cancer 
 
 
2. Any other current or previous malignancy within the 
past 5 years other than exceptions as determined 
by the opinion of the treating MD and PI, which 
include: 
• 
Adequately treated basal cell or squamous cell 
skin cancer 
• 
Carcinoma in situ of cervix 
• 
Prostate cancer with stable PSA level for >3 
years, or 
• 
Other neoplasm that, in the opinion of the 
treating MD and PI, will not interfere with study- 
specific endpoints 
 
 
3. Pregnant or nursing (per department of radiology 
policy) 
 
 
* All subject files must include supporting documentation to confirm subject eligibility. The 
method of confirmation can include, but is not limited to, laboratory test results, radiology test 
results, subject self-report, and medical record review. 
V. 
Statement of Eligibility 
By signing this form of this trial I verify that this subject is: 
eligible / 
ineligible for 
participation in the study. This study is approved by the Stanford Cancer Institute Scientific 
Review Committee, the IRB of record, and has finalized financial and contractual agreements as 
required by Stanford School of Medicine’s Research Management Group. 
 
Study Coordinator printed name: 
Date: 
Signature: 
Investigator printed name: 
Date: 
Signature: 
Triple-check reviewer printed name: 
Date: 
Signature: 


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Eligibility Checklist (Group 2: Smokers and Non-Smokers) 
I. 
Protocol Information 
 
Protocol Title: 18F-FSPG PET/CT and Integrated Biomarkers for Early Lung Cancer 
Detection in Patients with Indeterminate Pulmonary Nodules 
Group Group 2: Smokers and non-smokers 
eProtocol number: 
OnCore number: 
IRB-46607 
LUN0106 
Principal 
Investigator: Carina Mari Aparici, MD 
 
II. 
Subject Information 
 
Subject name / Unique ID: 
/ 
Gender 
Male 
Female 
 
III.  
Study Information 
Inclusion Criteria 
Prospective Participant Must MATCH 
ALL these Inclusion Criteria to be Eligible 
Yes 
No 
Supporting 
Documentation * 
1. Pulmonary nodule between the size of 7 to 30 mm. 
Subjects with multiple nodules may be eligible if the 
dominant nodule is 7 to 30 mm. 
 
 
2. ≥ 45 years old 
 
 
3. Documented informed consent 
 
 


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Exclusion Criteria 
 
Prospective Participants Must NOT Match 
ANY of These Exclusion Criteria 
Yes 
No 
Supporting 
Documentation * 
1. History or previous diagnosis of lung cancer 
 
 
2. Any other current or previous malignancy within the 
past 5 years other than exceptions as determined by 
the opinion of the treating MD and PI, which include: 
• 
Adequately treated basal cell or squamous cell 
skin cancer 
• 
Carcinoma in situ of cervix 
• 
Prostate cancer with stable PSA level for >3 
years, or 
• 
Other neoplasm that, in the opinion of the 
treating MD and PI, will not interfere with study- 
specific endpoints 
 
 
3. Pregnant or nursing (per department of radiology 
policy) 
 
 
* All subject files must include supporting documentation to confirm subject eligibility. The 
method of confirmation can include, but is not limited to, laboratory test results, radiology test 
results, subject self-report, and medical record review. 
V. 
Statement of Eligibility 
By signing this form of this trial I verify that this subject is: 
eligible / 
ineligible for 
participation in the study. This study is approved by the Stanford Cancer Institute Scientific 
Review Committee, the IRB of record, and has finalized financial and contractual agreements as 
required by Stanford School of Medicine’s Research Management Group. 
 
Study Coordinator printed name: 
Date: 
Signature: 
Investigator printed name: 
Date: 
Signature: 
Triple-check reviewer printed name: 
Date: 
Signature: 


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3.2. 
Informed Consent Process 
All participants must be provided a consent form describing the study with sufficient 
information for participants to make an informed decision regarding their participation. 
Participants must sign the IRB approved informed consent prior to participation in any study 
specific procedure. The participant must receive a copy of the signed and dated consent 
document. The original signed copy of the consent document must be retained in the 
medical record or research file. 
Study Timeline 
3.2.1. Primary Completion: 
The study will reach primary completion 36 months from the time the study opens to 
accrual. 
3.2.2. Study Completion: 
The study will reach study completion 60 months from the time the study opens to 
accrual. 
4. IMAGING AGENT AND PROCEDURE INFORMATION 
4.1. 
Imaging Agent and Imaging Procedure 
Patients enrolled in this study will undergo a one-time 18F-FSPG PET/CT procedure which 
includes a single IV injection of 18F-FSPG. Patients will also undergo one 18F-FDG PET/CT 
as part of their standard of care. The two PET/CT procedure will be scheduled > 24 hours 
apart to allow for imaging agent washout, and not more than two weeks apart. 
The nuclear physician or designee is responsible for ensuring that deliveries of the imaging 
agent and other materials from the manufacturing site are correctly received, recorded, 
handled, and stored safely and properly in accordance with all applicable regulatory 
guidelines, and used in accordance with this protocol. 
Unless otherwise agreed, imaging agent vials must be destroyed on-site after use. The 
transport containers have to be returned to the manufacturing site. A list of imaging agent or 
other materials that were returned, or destroyed, must be prepared and signed by the 
principal investigator or designee. If there are any discrepancies, an explanation for these 
should also be provided 
Physical, Chemical and Pharmaceutical Properties of the Imaging Agent 
IUPAC name: 
(S)- 4-(3-[18F]Fluoropropyl)-L-glutamic acid 
Chemical name: 
(2S, 4S)-2-Amino-4-(3-[18F]-fluoro propyl) pentane dioic acid 
Empirical formula: 
C8H14FNO4 
Molecular weight: 
206.2 g/mol 
The active pharmaceutical ingredient for PET/CT imaging is the compound 18F-FSPG that is 
labeled with the radioactive fluoride isotope 18F. 18F has a half-life of 110 minutes. The 
radioactive substance and the final imaging product are produced on-site at the study site 


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according to the radiolabeling and purification procedure described in the site Standard 
Operating Procedures (SOPs) and the Investigational New Drug application (IND). The 
Department of Chemistry, Manufacturing, Controls (CMC) personnel of Stanford will train 
qualified radiochemists/pharmacists with respect to the imaging agent production and 
handling. The precursor PI-020 and a non-radioactive standard used as a reference for 
Quality Assurance, and corresponding Certificates of Analysis will be provided by Piramal 
Imaging, SA. 
Each batch of 18F-FSPG produced must meet criteria listed in the specification for identity, 
purity, concentration, specific activity and pH before being released. Manufacturing and 
quality control testing will be checked and documented accordingly. Sterility tests will be 
conducted as control of the validated production process after release of the product 
according to the established procedures. 
The final product will be formulated as sterile solution for IV injection. The radioactivity of 
the final product will be verified before injection using a suitable counter, as established on 
site. 
Further details can be found in the Piramal Investigator's Brochure. 
Dosage and Administration 
Study participants will be administered 18F-FSPG under the direct supervision of a nuclear 
physician or designee. For administration of 18F-FSPG, access into a large vein (e.g., 
antecubital vein) should be established using a suitable indwelling catheter. To avoid 
extravasation of 18F-FSPG, correct localization of the catheter must be ensured by a test 
injection of normal saline prior to the injection of 18F-FSPG. 
Each study participant will receive a single IV injection of 18F-FSPG with a total activity 
amounting to 300 MBq (8.1 mCi) ± 10%. This single IV injection will contain a maximum 
mass dose of the diagnostic test agent (total: radioactive plus non-radioactive “cold” 
substance) of no more than 50 µg and a total volume of up to 10 mL. 18F-FSPG will be 
administered manually via IV injection followed by a 10 mL saline flush. The PET/CT scan 
will be conducted about 60 minutes after the injection of 18F-FSPG. 
Packaging and Labeling 
18F-FSPG for Injection will be provided as a sterile solution in a glass vial, contained in a 
lead-shielded transport container. Provided is a representation of the 18F-FSPG for Injection 
label to be used on both the vial and the lead-shielded transport container. 


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Imaging Agent Logistics and Accountability 
The imaging agent will be prepared at Stanford at the following facility under the supervision 
of Director Frederick T Chin, PhD: 
Cyclotron & Radiochemistry Facility 
Lucas Building 
Molecular Imaging Program at Stanford (MIPS) 
1201 Welch Road, Room PS049 
Stanford, CA 94305 
P: 650-725-4182 
F: 650-618-0415 
The imaging agent will be requested via a standard online radiotracer request form received 
by the MIPS Cyclotron & Radiochemistry Facility at Stanford University. The agent will be 
hand delivered from the Radiochemistry Facility at the Lucas Center to the Hot Lab in the 
Nuclear Medicine and Molecular Imaging Clinic at Stanford Hospital. 
Appropriate documentation (for order/receipt, dosage instructions and release for human 
use) will be provided with each delivery of imaging agent which will contain the batch 
number, time of preparation, and radioactive concentration of injection (MBq/mL) at the time 
of calibration preparation. The final quality control processes for the imaging agent will 
occur and be documented before the substance is administered to the subject at the 
imaging clinic. The qualified person at the manufacturing site will ensure that the product 
quality meets the defined criteria and will declare this in a document for release, to be 
received by the investigator (or designated personnel) at the imaging clinic. The imaging 
agent will not be administered to the subject without release for human use. 
The investigator (or designated personnel) will confirm receipt of the imaging agent in writing 
and will use the imaging agent only within the framework of this clinical study and in 
accordance with this study protocol. For each subject he/she will keep a record of the 
imaging agent dispensed including the tear off label of the dispensed vial, a printout 
providing relevant parameters of synthesis and formulation of the imaging agent, and all 
other accompanying forms to the imaging agent. These documents are to be filed in the 
investigator site file. 
Receipt, distribution, and return of the imaging agent must be properly documented on the 
forms provided by the manufacturer giving the following information: study protocol number, 
sender, receiver, date, mode of transport, quantity, batch number, expiration date, and 
retest date, if applicable. 
5. STUDY PROCEDURES 
Phlebotomy: 
Blood will be collected once by a standard venipuncture. Blood will be collected in 
chemistry tubes (EDTA) and cell preservative tubes (Streck) to be stored in the Canary 
Center at Stanford biorepository and to be sent to our Boston University collaborators for 
processing and analysis. A total of 30 mL will be collected in a one-time blood draw. Blood 
draw will take place within 1 month after the patient has been consented. 


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Nasal Brushing: 
Patient will be asked to blow their nose. A small speculum is used to widen the nostril and a 
tiny brush (the size of a Q tip) is put in through the speculum and rotated for 3 seconds. 
This brush is then removed, and a second brush is inserted and rotated for 3 seconds. 
Finally, the speculum and brush are removed from the nose. Nasal brushing will take place 
within 1 month after the patient has been consented. 
18F-FSPG PET/CT scan: 
The patient will be injected with the radiotracer and allowed to rest for about 60 minutes. 
He/she will then be placed in the PET/CT and a static whole-body scan will be obtained from 
the vertex of the skull to the mid-thighs, starting at 60 (± 10) minutes after radiotracer 
injection. 
6. STUDY CALENDAR 
 
Visit 1 
Within 1 month 
from Visit 1 
(can be Visit 2/3) 
Visit 2 or 3* 
Visit 3 or 2* 
Within 
24 to 72 hours after 
18F-FSPG PET/CT 
Informed consent 
X 
Nasal Brushing 
X 
Blood draw 
X 
18F-FDG PET/CT 
X 
18F-FSPG PET/CT 
X 
Patient follow-up 
X 
 
* & 
: PET/CT exams is not specified and may be reversed. PET/CT exams will be 
scheduled at least 24 hours apart, and no more than 2 weeks apart. 
 
7. COMPENSATION 
Study participants will be compensated with a total of $500 for the time it takes them to 
complete the study procedures, including time and transportation for the additional visit to 
the clinic for the PET/CT procedure. 
8. ADVERSE EVENTS AND REPORTING PROCEDURES 
8.1. 
Risks and Potential Adverse Events 
The risk associated with phlebotomy is small and includes discomfort, a bruise at the point 
where the blood is taken, redness, infection, and a rare risk of fainting. The risk associated 


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with the nasal brushing procedure is also small and includes minor discomfort and 
temporary nose bleed. 
18F-FSPG has been administered to over 65 cancer patients world-wide with no adverse 
events reported. As such, there are no major risks that are known or expected with this 
radiopharmaceutical. However, general risks to keep in mind include the radiation 
exposure. The expected radiation exposure of an 18F-FSPG scan in this study is expected 
to be similar to or less than that of an 18F-FDG scan. Other risks to patients are mainly 
related to the intravenous (IV) injection. Although the risk is small, intravenous injection can 
cause infection, injection site discomfort, and bruising. 
8.2. 
Adverse Event Reporting 
Patients will be contacted for follow up within 24 to 72hours after the 18F-FSPG PET/CT, 
Adverse events will be graded according to CTCAE v5. Both Serious and Non-Serious 
Adverse Events will be clearly noted in source documentation. The Protocol Director (PD) 
or designee will assess each Adverse Event (AE) to determine whether it is unexpected 
according to the Informed Consent, Protocol Document, or Investigator’s Brochures, and 
related to the investigation. 
9. REGULATORY CONSIDERATIONS 
9.1. 
Investigational New Drug Application (IND) 
This study will be submitted to 18F-FSPG IND 125516, held by Dr Andrei Iagaru. 
9.2. 
Institutional Review of Protocol 
The protocol, the proposed informed consent and all forms of participant information related 
to the study (e.g. advertisements used to recruit participants) will be reviewed and approved 
by the Stanford IRB and Scientific Review Committee (SRC). Any changes made to the 
protocol will be submitted as a modification and will be approved by the IRB and SRC prior 
to implementation. The Protocol Director will disseminate the protocol amendment 
information to all participating investigators. 
Sample management 
PET imaging analysis will be performed at Stanford. The blood and nasal samples will be 
transferred to Boston University for the RNA and DNA sequencing analyses. 
9.3. 
Data Management Plan 
We will use OnCore and REDCap for data storage and all paper documents will be stored in 
a binder in a locked cabinet on Stanford premises. 
9.4. 
Data and Safety Monitoring Plan 
During the clinical investigation, the Protocol Director will evaluate the progress of the trial, 
including periodic assessments of data quality and timeliness, participant recruitment, 
accrual and retention, participant risk versus benefit, and other factors that can affect study 
outcome. The study team meets bi-weekly to review the study conduct and status. 
The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will audit 
study related activities at least annually in accordance with the DSMC SOP to determine 


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whether the study has been conducted in accordance with the protocol, local standard 
operating procedures, FDA regulations, and Good Clinical Practice (GCP).  This may 
include review of regulatory binders, case report forms, eligibility checklists, and source 
documents. In addition, the DSMC will regularly review serious adverse events and protocol 
deviations associated with the research to ensure the protection of human subjects. Results 
of DSMC audits will be communicated to the IRB and the appropriate regulatory authorities 
at the time of continuing review, or in an expedited fashion, as needed. 
10. MEASUREMENTS 
10.1. Primary Outcome Measure (ClinicalTrials.gov) 
    The primary outcome is specificity of 18F-FSPG to discriminate between benign and 
malignant lung nodules, defined as the proportion of benign cases judged to be benign.  With 
an expected 60 benign cases, an observed 90% specificity would have a 95% confidence 
interval of 79% to 96%.  An observed specificity of 75% would have a confidence interval of 
62-85%. 
If a patient has multiple nodules, the per-patient assessment will be based on the 
dominant nodule only, defined as the largest nodule. 
Outcome Title: 18F-FSPG specificity for malignant lung nodules. 
Outcome Description: 18F-FSPG accumulation in lung nodules will be assessed. 
The observed FSPG specificity will be assessed against a fixed value of 75%. 
Timeframe: Up to 5 years. 
Safety Issue: No. 
 
 
10.2. Secondary Outcome Measure (ClinicalTrials.gov) 
The secondary outcome is improved performance of an integrated prediction model to 
discriminate between benign and malignant lung nodules, compared with a clinical 
prediction model. 
Outcome Title: Improved prediction model for lung nodules 
Outcome Description: Improved performance is defined as a p < 0.05 increase in 
the C statistic determined using DeLong’s test for correlated ROC curves. 
Timeframe: Up to 5 years. 
Safety Issue: No. 
 
10.3. Measurement Methods 
For RNA and DNA sequencing the blood and nasal samples will be transferred to Boston 
University. PET imaging analysis will be performed at Stanford. 
Total RNA-seq of Nasal Brushings: RNA sequencing libraries will be prepared from total 
RNA samples using Illumina® TruSeq® Stranded Total RNA Library Preparation Kit. The 
libraries from individual samples will be multiplexed in groups of 4 for cluster generation on 


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the Illumina® cBot® using Illumina® TruSeq® Paired-End Cluster Kit. Each sample will be 
sequenced on the Illumina® HiSeq® 2500 to generate paired-end 75 nucleotide reads. 
De-multiplexing and creation of FASTQ files will be performed using Illumina CASAVA 
software. RNA-Seq reads will be aligned to the human genome (hg19) using STAR, quality 
metrics will be calculated using RSeQC, and gene and transcript expression levels will be 
summarized using RSEM and Ensembl annotation. Gene and transcript filtering will be 
conducted on normalized counts using the mixture model in the SCAN.UPC R package. 
R software will be used to conduct all further analyses.  Batch correction will be done using 
a modified version of our SCAN algorithm29 that is adapted to work with sequencing counts. 
Single Cell RNA-seq of Nasal brushing: Nasal brushings will be subject to Florescent 
Activated Cell Sorting (FACS) (10 markers specific to either immune or epithelial cells) and 
sorted into single cells. Plates of single cells will be processed for single cell RNA 
sequencing using the CEL-Seq2 protocol, 75 bp single-end reads (400K/cell), on 
200 single cells/sample. 
Circulating tumor DNA: ctDNA lung cancer biomarker will be developed using plasma 
samples available on 380 patients (n = 190 each cases and controls). This biomarker will 
then be validated on the remaining 200 samples. We will analyze plasma samples using 
TEC-seq. Tumor WES sequencing will be performed on a subset of training set (n-150) to 
confirm source of ctDNA. Using the same genomic libraries utilized for TEC-seq, we will 
also perform whole genome analyses to identify chromosomal abnormalities using the 
Digital Karyotyping approach. TEC-seq and whole exome seq profile somatic mutations 
which is not considered genetic. 
PET Imaging: Patients will be imaged by 18F-FDG PET/CT and 
18F-FSPG PET/CT. Uncorrected maximum lesion intensity (SUVmax) along with qualitative 
measures (absent, minimal, moderate, or high uptake) will be recorded. These data will be 
analyzed for lung cancer diagnosis using our prospective cohort study design The person 
assessing SUVmax values and making the decisions about “positive” or “negative” will be 
blinded to the cancer status of the patient. We will maintain this by keeping the image 
reader blind to the patient information. 
11. STATISTICAL CONSIDERATIONS 
11.1. Statistical Design and Data Analysis 
 
Clinical diagnosis is based on 1) histopathology of biopsy/surgical specimen or 2) surveillance by 
CT scans for a period of 2 years  to confirm that there is no growth of the nodule. Meta-analysis 
shows that 18F-FDG has a sensitivity and specificity of 89% and 75%  respectively (16). We 
hypothesize that 18F-FSPG is more specific. With an expected 90% specificity for diagnosis with 
18F-FSPG, a sample size of 60 will have 90% power at an alpha-level of 0.05 to demonstrate  a 
significant increase in specificity from a fixed value of 75%. 
 
 
Integrated predictions models: 
Our biomarker discovery and validation will use samples from 930 patients in the intended 
use population collected prior to diagnosis; and subsample from all available cancer and 
non-cancer patients. Through our experience with the NCI Early Detection Research 
Network (EDRN), we have a detailed plan for biomarker discovery and validation, which is 
briefly summarized here. 


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Identification of candidate genes from nasal total RNA-seq data:  We will initially select 
20 to 40 candidate genes that significantly discriminate between cases (n = 100) and 
controls (n = 100). We will prioritize candidates to: 1) represent cancer-associated gene 
co-expression patterns, 2) genes whose expression is independent of clinical factors, and 
genes in significantly enriched functional categories. 
Using single cell nasal RNA-seq to refine the nasal gene expression biomarker assay: We 
hypothesize that a subset of airway cells harbor lung-cancer associated gene expression 
differences (or that the distribution of cell types might distinguish the airway of cancer 
patients). We will perform scRNA-seq on cells collected prospectively from 200 patients 
(n = 100 each cases and controls). We will identify cell subpopulations using Celda and test 
for cell type-specific alterations associated with subtype, prognosis or disease activity using 
a strategy similar to that used for bulk RNA-seq data. Additionally, we will test for 
differences in cell population frequency associated with prognosis or disease activity; and 
also determine which cell subpopulations express the prognosis and disease activity 
associated genes identified in the bulk RNA-seq to understand the cellular architecture of 
these disease signatures. For biomarker development, we will interrogate the cellular 
architecture of the expression of the nasal biomarker genes. If biomarker gene expression 
localizes to specific cells, we would subsequently explore whether enriching for these cells 
improves biomarker performance.  Alternatively, if the frequency of a nasal cell type differs 
in patients with lung cancer, we would explore whether quantifying this cell-type’s frequency 
could serve as a lung cancer biomarker. 
Identification of CT features: Similar to the gene expression analysis, our initial goal is to 
identify 5 to 10 candidate semantic or quantitative imaging features that optimally 
discriminate cases and controls. We will centrally process thin-section CT images resulting 
in a high-dimensional dataset of image features based on CAD detection and nodule 
segmentation, and quantitative feature extraction. Semantic analysis of CT scans will be 
conducted by thoracic imagers using an illustrated lexicon to maximize inter-reader 
agreement. A convolutional neural network (CNN) will derive synthetic quantitative 
measures predictive of cancer status via cross validation. The most cancer-discriminating 
quantitative and semantic features will be selected for downstream analysis. 
Data Integration: Using a new set of 150 patients (75 cases and 75 controls), we will subset 
candidate genes and imaging features based on whether they improve (significantly higher 
ROC curve AUC) clinical lung cancer risk models with the goal of picking no more than 
10 genes and 5 imaging features, and prioritizing genes least correlated with imaging 
features or the ctDNA biomarker. We will next use data from 380 new patients (n = 190 
each cases and controls) to train and “lock down” models prior to validation. Model building 
will use a logistic regression framework (incorporating LASSO and ridge regression) and 
cross-validation. We will build models stepwise from clinical-variable-only models by adding 
additional biomarker datatypes (gene expression, imaging, and / or the ctDNA biomarker). 
Cross validation will determine the gain in diagnostic performance from each additional 
datatype, and combinations that do not improve performance will be eliminated. These 
locked down models will be validated in the remaining samples (n = 200). The primary 
endpoint will be calculated after every patient has either completed two years of follow up, 
been diagnosed positive, or died, whichever comes first. The primary endpoint for 
validation of this prediction model will be replication of improved performance. Exploratory 


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endpoints will determine the range of pre-test probabilities for which the models have 
potential clinical utility. 
11.2. Sample Size 
 
Primary outcome: To compare 18F-FSPG PET/CT imaging with 18F-FDG PET/CT imaging 
for indeterminate lung nodules we will evaluate 120 patients. We estimate that 
approximately 60 of the patients will be diagnosed with lung cancer after complete 
diagnostic work-up and ~60 will not have lung cancer. Meta-analysis shows that 18F-FDG 
has a sensitivity and specificity of 89% and 75% respectively (16). We hypothesize that 18F-
FSPG is more specific. With an expected 90% specificity for diagnosis with 18F-FSPG, a 
sample size of 60 will have 90% power at an alpha-level of 0.05 to demonstrate a significant 
increase in specificity from a fixed value of 75%. 
 
Secondary outcome: In total the SU2C consortium cohort will be comprised of 930 study 
participants. Our Stanford group will contribute 120 (60 cases and 60 controls) to the larger 
sample set. Breakdown of the 930 patients are as follows. For the discovery step, sample 
size of 100 cases and 100 controls provides 80% power to detect RNA markers with effect 
sizes of at least 0.52 assuming that we will control the false discovery rate at 10% and 5% of 
markers are differentially expressed. For the refinement step, 75 cases and 75 controls 
provides 81% power to detect markers with a ROC AUC of at least 0.63 assuming an alpha 
level of 0.05. No correction for the multiple hypothesis testing is planned as we will 
re-evaluate top candidates. The sample size of 190 of each group for model building will 
support the following: 
1. This sample size will be sufficient to include approximately 12 to 20 variables overall 
between clinical, imaging, ctDNA and gene expression markers based on conventional 
rules of thumb of 10 to 15 subjects per group per variable; 
2. This will allow us to estimate the AUC for each model with a precision of approximately 
4.5% (95% CI); 
3. Provide 80% power for detecting delta AUCs between models of 0.06 assuming model 
correlation of 0.6. 
For the model testing, 100 subjects in each group will provide AUC precision of ± 0.06 (and 
a precision of between 0.06 and 0.08 for the sensitivity and specificity), as well as a 80% 
power to detect differences in AUCs between models of 0.09. IRBs at the other sites have 
approved the collection of biospecimens and use of clinical / imaging data for this model 
development and validation work. 
11.3. Accrual estimates 
In our clinic on average 30 patients per month are seen with lung nodules. Of these patients 
around 50% have truly indeterminate lung nodules for which clinical management is 
uncertain. We estimate that about 20% of the eligible candidates will consent to participate 
in the study, leading to an accrual of circa 3 patients per month. We expect to be able to 
complete the study (50 patients) within 3 years. 
After the first 2.5 years of the study, we will assess the long-term follow up rate and add 


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additional patients if accrual is not sufficient.  We will not do an interim statistical analysis. 
 
11.4. Criteria for future studies 
If 18F-FSPG PET/CT imaging has a higher specificity for detecting malignant lung nodules 
compared to 18F-FDG PET/CT, a larger study will be planned. 
 
12.  REFERENCES 
1. van den Heuvel AP, Jing J, Wooster RF, Bachman KE. Analysis of glutamine dependency in 
non-small cell lung cancer: GLS1 splice variant GAC is essential for cancer cell growth. 
Cancer Biol Ther. 2012;13(12):1185-94. 
2. Baek S, Choi C-M, Ahn SH, Lee JW, Gong G, Ryu J-S, et al. Exploratory clinical trial of 
(4S)-4-(3-[18F]fluoropropyl)-L-glutamate for imaging xC- transporter using positron emission 
tomography in patients with non-small cell lung or breast cancer. Clinical Cancer Research: An 
Official Journal of the American Association for Cancer Research. 2012;18:5427-37. 
3. Gould MK, Ananth L, Barnett PG, Group VASCS. A clinical model to estimate the pretest 
probability of lung cancer in patients with solitary pulmonary nodules. Chest. 2007;131:383-8. 
4. McWilliams A, Tammemagi MC, Mayo JR, Roberts H, Liu G, Soghrati K, et al. Probability of 
cancer in pulmonary nodules detected on first screening CT. The New England Journal of 
Medicine. 2013;369:910-9. 
5. Leary RJ, Sausen M, Kinde I, Papadopoulos N, Carpten JD, Craig D, et al. Detection of 
chromosomal alterations in the circulation of cancer patients with whole-genome sequencing. 
Science Translational Medicine. 2012;4. 
6. Perez-Rogers JF, Gerrein J, Anderlind C, Liu G, Zhang S, Alekseyev Y, et al. Shared Gene 
Expression Alterations in Nasal and Bronchial Epithelium for Lung Cancer Detection. JNCI: 
Journal of the National Cancer Institute. 2017;109. 
7. Silvestri GA, Vachani A, Whitney D, Elashoff M, Porta Smith K, Ferguson JS, et al. A Bronchial 
Genomic Classifier for the Diagnostic Evaluation of Lung Cancer. The New England Journal of 
Medicine. 2015;373:243-51. 
8. Whitney D, Elashoff M, Porta-Smith K, Gower A, Vachani A, Ferguson J, et al. Derivation of a 
gene-expression classifier in a prospective study of patients undergoing bronchoscopy for 
suspicion of lung cancer. BMC Medical Genomics. 2015. 
9. Hashimshony T, Senderovich N, Avital G, Klochendler A, de Leeuw Y, Anavy L, et al. 
CEL-Seq2: sensitive highly-multiplexed single-cell RNA-Seq. Genome Biology. 2016;17:77. 
10. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646-74. 
11. Banjac A, Perisic T, Sato H, Seiler A, Bannai S, Weiss N, et al. The cystine/cysteine cycle: a 
redox cycle regulating susceptibility versus resistance to cell death. Oncogene. 
2008;27:1618-28. 
12. Huang Y, Dai Z, Barbacioru C, Sadée W. Cystine-glutamate transporter SLC7A11 in cancer 
chemosensitivity and chemoresistance. Cancer Research. 2005;65:7446-54. 


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13. Lyons SA, Chung WJ, Weaver AK, Ogunrinu T, Sontheimer H. Autocrine glutamate signaling 
promotes glioma cell invasion. Cancer Research. 2007;67:9463-71. 
14. Haberkorn U, Ziegler SI, Oberdorfer F, Trojan H, Haag D, Peschke P, et al. FDG uptake, tumor 
proliferation and expression of glycolysis associated genes in animal tumor models. Nuclear 
Medicine and Biology. 1994;21:827-34. 
15. Mosci C, Kumar M, Smolarz K, Koglin N, Stephens AW, Schwaiger M, et al. Characterization of 
Physiologic (18)F FSPG Uptake in Healthy Volunteers. Radiology. 2016;279:898-905. 
16. Deppen SA, Blume JD, Kensinger CD, Morgan AM, Aldrich MC, Massion PP, et al. Accuracy of 
FDG-PET to diagnose lung cancer in areas with infectious lung disease: a meta-analysis. 
JAMA. 2014;312:1227-36. 

ICF_002.pdf: 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Carina Mari Aparici, MD 
IRB# 46607 
Protocol Title:  
18F-FSPG PET/CT and Integrated Biomarkers for Early Lung Cancer Detection in Patients with 
Indeterminate Pulmonary Nodules 
Page 1 of 19 
Aparici--Bedi / IRB-46607 ICF_13 June 2022 
IRB Use Only 
Approval Date:   October 24, 2023 
Expiration Date: October 24, 2024 
Participant ID: 
Are you participating in any other research studies?  _____ Yes  _____No 
INTRODUCTION TO RESEARCH STUDIES 
You are invited to voluntarily participate in a research study of an imaging agent, or 
“radiotracer,” called 18F-FSPG, also known as 18F-fluoropropyl-glutamic acid, being 
conducted by Carina Mari Aparici, MD, and Brian Shaller, MD, at the Stanford Cancer 
Center.  You were selected as a possible participant in this study because you have lung 
nodules of unknown cause.  
This document is to be used as a guide for a discussion between you and your 
Study Doctor and the study team.  This form, called an informed consent document, was 
designed to help you understand why this study is being done;  what part of the study is 
“research” or “experimental;”  what will be asked of you if you choose to participate;  
possible risks;  any inconveniences or discomforts you may experience;  and other 
important information.  This document is intended to provide the information that a 
potential participant might want to have in order to make an informed decision about 
whether to participate in the research study.  If you have any questions or would like 
additional information, please ask the person obtaining consent or any other member of 
the study team.  
If you choose to participate, this form may also be helpful as a reference or reminder 
about your role in the study, and whom to contact if you have any questions at any time 
during your participation.  If you wish, you can also discuss this study and your role with 
your family doctor or medical provider.  
PURPOSE OF RESEARCH 
The study team hopes to learn if the experimental agent 18F-FSPG is a better imaging 
agent for determining if lung nodules are cancerous than the current standard of care, 
18F-FDG.  
Your normal medical care for such an evaluation would be a single imaging scan with 
18F-FDG.  The study team would like to compare the results of that scan with a scan 
using 18F-FSPG as the imaging agent.  
The use of 18F-FSPG in this research study is investigational (“experimental”).  The word 
“investigational” means that 18F-FSPG is not approved by the US Food and Drug 
Administration (FDA) for use in the United States as an imaging agent.  This study is 
being conducted under an application submitted to FDA, called an “Investigational New 
Drug Application” or “IND.”  The extra scan and the associated visits are the only parts of 
this study that are not part of your regular medical care.  
If you decide to terminate your participation in this study, you should notify Dr Shaller at 
650-725-5071, or Dr Carina M Aparici at 650-723-6855.
NCT03824535


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Carina Mari Aparici, MD 
IRB# 46607 
Protocol Title:   
18F-FSPG PET/CT and Integrated Biomarkers for Early Lung Cancer Detection in Patients with 
Indeterminate Pulmonary Nodules 
 
 
 
 
 
 
Page 2 of 19 
 
Aparici--Bedi / IRB-46607 ICF_13 June 2022 
IRB Use Only 
Approval Date:   October 24, 2023 
Expiration Date: October 24, 2024 
Participant ID: 
This research study is looking for about 120 people with lung nodules of unknown cause 
to participate.  The study is being done only at Stanford University. 
VOLUNTARY PARTICIPATION  
Your participation in this study is entirely voluntary.  Your decision not to participate will 
not have any negative effect on you or your medical care.  You can decide to participate 
now, but withdraw your consent later and stop being in the study without any loss of 
benefits or medical care to which you are entitled.  
DURATION OF STUDY INVOLVEMENT  
It is planned that each participant will take part in this study for about 1 month, 
consisting of the day of the scan and follow-up in about 30 days. 
PROCEDURES 
Research studies are usually dividing into at least 3 parts, typically consisting of: 
1. Testing to see if you are eligible to participate in the study (“Screening”) 
2. Testing during the study to monitor your health and the effects of the study 
treatment (“Study Evaluation Procedures”), and  
3. Evaluation after the diagnostic study procedures are complete (“Follow-up”).  
Testing/procedures for each of these parts are described separately below.  Most of 
these examinations, tests, or procedures will be part of your regular medical care, and/or 
and may be done even if you do not join the study.  
Before you join this study, the Study Doctors and/or the research study team will review 
this document with you, and ask you to sign this informed consent document.  After you 
have signed this document, and received a signed copy, the study will begin with a 
Screening Visit.  
Screening Visit 
If you choose to participate, the first activity will be screening and consent at Visit 1.  
During this visit, the study will be discussed and you will be asked to sign this consent 
form.   
Location:  The location of the Screening Visit will be at: 
Pulmonary Clinic, Boswell Building, 1st floor 
Stanford Hospital 
300 Pasteur Dr  
Stanford, CA  94305  
Phone 650-725-7061 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Carina Mari Aparici, MD 
IRB# 46607 
Protocol Title:   
18F-FSPG PET/CT and Integrated Biomarkers for Early Lung Cancer Detection in Patients with 
Indeterminate Pulmonary Nodules 
 
 
 
 
 
 
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Expiration Date: October 24, 2024 
Participant ID: 
Women of Childbearing Potential 
If you are pregnant or currently breast-feeding, you may not participate in this study.  It is 
not known whether the imaging agent is safe for the fetus (unborn child) or a 
breast-fed baby.  
Administration of Study Agents and Scans 
All participants will receive the same imaging agents and have the same tests.  For this 
part of the study, you will undergo 2 medical imaging scans, one conducted with 
18F-FSPG as the imaging agent, and the other with 18F-FDG.  These scans may be 
conducted in any order, but they should be conducted at least 24 hours (1 day) apart, 
and within 30 days of each other.  At one of these visits, you will provide a small blood 
sample and a nasal brushing.  Your samples will be sent outside of Stanford for 
analysis. 
Blood collection:  Blood collection will typically be from a vein in your arm, using a blood 
collection needle.  This is called venipuncture.  If you have an implanted venous access 
port, this may be used for blood collection.  Standard aseptic (clean) techniques will be 
used.  About 2 tablespoons (30 mLs) of blood will be collected. 
Nasal brushing:  A nasal brushing will be conducted with a small brush about the size 
cotton swab.  This will be done twice in a row.  
Medical imaging scans:  The imaging for this study is a combination scan, based on 
positron emission tomography (PET) and computed tomography (CT).  As a 
combination scan, this is called a PET/CT scan.  You will have 2 PET/CT scans, one 
that uses 18F-FDG, and one that uses 18F-FSPG as the imaging agent.  
A PET scan is a computerized image that looks at blood flow and the extent of 
metabolic activity in your entire body.  PET scans use a radioactive material called a 
“radio-isotope;”  “radio-tracer;”  or “radiolabel.”  The radio-isotope is attached to 
glucose (sugar), and combined this is the radiolabel.  A tourniquet will be applied to 
your arm or leg to help find a vein, and a small amount of the radioactive 18F-FDG or 
18F-FSPG will be injected into a vein about 1 hour before the scan.  The radiolabel 
accumulates in areas of the body that are metabolically active, and this accumulation 
is detected by the scanner.  Tumors are usually very metabolically active, more so 
than normal tissues.  You will be asked to lie on a long narrow bench for a 
few minutes while the machine performs the scan.  You may experience some 
discomfort or anxiety from being in the confined space.  If this bothers you too much, 
the study team may provide you with a medication to help you stay calm.  The camera 
will record the tracer’s signal as it travels through your body.  
A computed tomography (CT) scan (an “X-ray”) will be performed without contrast 
(except for the PET agent) according to standard practice, and is a computerized 
imaging procedure that makes many cross-sectional images (often called slices), both 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Carina Mari Aparici, MD 
IRB# 46607 
Protocol Title:   
18F-FSPG PET/CT and Integrated Biomarkers for Early Lung Cancer Detection in Patients with 
Indeterminate Pulmonary Nodules 
 
 
 
 
 
 
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Expiration Date: October 24, 2024 
Participant ID: 
horizontally and vertically, of the body.  For this study, the CT scan will be used to 
look at the anatomy of your entire body.  You will need to remove all jewelry, 
piercings, and other metal items.  IT IS VERY IMPORTANT THAT YOU 
IMMEDIATELY TELL THE STUDY DOCTORS AND/OR THE CT TECHNICIAN 
if any of the following apply to you:  
 You are or could be pregnant  
 You have, or previously had, kidney problems.  
 You are taking Glucophage (metformin)   
 You have recently taken or received barium (“barium study”) or bismuth, or 
have recently taken Pepto-Bismol; Kaopectate; Maalox; Bismatrol; or other 
digestive aids  
 You have a cardiac pacemaker or any other biomedical device, such as 
surgical clips, pins; screws; or metal plates in or on your body. 
 You have any body piercings  
 In some cases, these could mean you should not have a CT scan performed  
The imaging for the CT signal is obtained in conjunction with the scan described for 
the PET scan and will provide the doctors with information about your body.  You will 
be asked to lie still on a long narrow bench, or scanner bed, for a few minutes.  A 
strap and/or pillows may be placed across your body to prevent movement so that the 
X-ray picture will be clear.  The scanner bed you are on will then slide into a large, 
tunnel-shaped machine.  You will be able to see the CT technician during the entire 
procedure, and there are microphones and speakers so you can communicate with 
the CT technician.  You will have a call button.  You will be asked not to move during 
the scan and to relax and breathe normally.  You may experience some discomfort or 
anxiety from being in the confined space.  If this bothers you too much, the study team 
may provide you with a medication to help you stay calm.  During the CT scan 
procedure, the scanner will rotate around you, and make clicking sounds, which is 
normal.  Tell the CT technician if you start to feel unusual, especially if you have a 
flushing sensation; a salty or metallic taste; a headache; and/or nausea / vomiting.  
These effects usually last for a few moments.  Tell the CT technician immediately if 
you have any breathing difficulties; sweating; numbness; or heart palpitations.  When 
the CT scan procedure and follow-up is finished, you may immediately resume your 
usual activities and diet.  
PET/CT scan:  PET scans are commonly combined with CT scans to get a better 
image of the inside of your body.  These procedures were described above.  This 
study uses both PET scans and CT scans in a combined procedure called a 
PET/CT scan.  The entire procedure of the combined PET/CT scan will take about 
30 to 60 minutes. 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Carina Mari Aparici, MD 
IRB# 46607 
Protocol Title:   
18F-FSPG PET/CT and Integrated Biomarkers for Early Lung Cancer Detection in Patients with 
Indeterminate Pulmonary Nodules 
 
 
 
 
 
 
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Expiration Date: October 24, 2024 
Participant ID: 
Location:  The location of the Study Visits will be at the Nuclear Medicine and 
Molecular Imaging Clinic.  
Nuclear Medicine and Molecular Imaging Clinic 
Stanford Hospital, 2nd floor 
300 Pasteur Dr  
Stanford, CA  94305  
Phone 650-723-6855  
Study Follow-Up Procedures 
You will be contacted within 24 to 72 hours after the 18F-FSPG PET/CT scan for 
follow-up.  This contact will probably occur by phone.  
Your Tissue / Data Samples for Research and Genetic Testing  
Research using tissue, such as your blood sample and the nasal swaps, is an important 
way to try to understand human disease.  Sometimes, research may include the testing 
and study of genes, also known as DNA, and related materials called RNA, proteins, 
and/or metabolites.  This type of testing is also called “genetic analysis” or called 
“pharmacogenomic research.”  You are being given this information because the 
Study Doctors want to include your blood sample and the nasal swaps in a research 
project and because they want to save the samples for future research.   
There are several things you should know before participating in this study and allowing 
your blood and nasal swaps to be studied.  This subject is complicated, and there are 
many considerations.  Ask for more information if you do not understand any part of this 
information.  
Genes are in every cell of your body.  Your genes were inherited from your 
biological parents and carry instructions for the body to grow, develop, and survive.  
Genes are made of a substance called DNA.  Most genes and DNA are identical among 
human beings, but there are small variations between different people.  These small 
genetic differences are why people have their own unique characteristics, such 
hair color, eye color, height, and other characteristics.  Some traits affected by genetics 
are not visible, such as why different people have different responses, including 
side effects, to the same agent, or are more likely to get certain diseases or conditions.  
The proteins in your body were determined by your genes, and control how your body 
works.  Differences in genes and therefore proteins can affect the way a disease 
develops, the way drugs act against the disease, or the way your body uses the 
drugs/imaging agents.  
The purpose of this type of research is to understand the cause and detection of 
disease, such as cancer.  In this study, the genetic research is being done to help 
improve the identification of cancer in individuals who have lung nodules of unknown 
cause.  


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Carina Mari Aparici, MD 
IRB# 46607 
Protocol Title:   
18F-FSPG PET/CT and Integrated Biomarkers for Early Lung Cancer Detection in Patients with 
Indeterminate Pulmonary Nodules 
 
 
 
 
 
 
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Expiration Date: October 24, 2024 
Participant ID: 
You are not required to agree to provide the sample for this genetic testing, but 
agreeing to provide theses sample is required to participate in this study.   
The samples collected in this study may be used for future research projects, including 
projects that are undetermined and may include “full genome sequencing” (ie, all your 
genes).   
The data from your sample for this genetic research project will be used for research 
purposes only.  This genetic research sample may be used for additional future 
undetermined research analyses including other cancer studies or with a group of other 
patients’ samples to determine the natural difference in genes and proteins in groups of 
people with cancer;  or to develop new gene research techniques; or in projects that 
may include “full genome sequencing” (ie, all your genes).  The sample and data 
generated from them will be held by sponsor or their partners for many years or specify 
the indicated term, eg, for up to 50 years.  These samples, and the data generated from 
them, may be shared with other researchers or entered into databases, provided 
confidentiality is upheld (you are not otherwise directly identified), and they are used 
only for research on the topics described in this document.  The information in these 
databases may be kept forever, however, information that could directly identify you will 
not be included in these databases.  
Although you will be told the results of study tests that are part of your regular 
medical care, the genetic testing described here will not be used for decisions about 
your medical care, and there may be no results from this genetic research for 
many years, therefore the results of the genetic testing may not be given to you, your 
doctor, or any other staff at the study center.  
You have the right to refuse to allow your tissues to be studied now or saved for future 
study.  You may withdraw from this study at any time.  The Study Doctors might retain 
the identified samples, eg, as part of your routine clinical care, but not for additional 
research.  
Your samples will be stored and identified by your unique study number, but not your 
name. 
Providing genetic information to others  
Sometimes patients have been required to furnish information from genetic testing for 
health insurance, life insurance, and/or a job.  A Federal law, the Genetic Information 
Nondiscrimination Act of 2008 (GINA), generally makes it illegal for health insurance 
companies, group health plans, and employers with 15 or more employees to 
discriminate against you based on your genetic information.  
Be aware that that GINA 2008 does not specifically protect you against 
genetic discrimination by companies that sell life insurance;  disability insurance;  or 
long-term care insurance.  


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Carina Mari Aparici, MD 
IRB# 46607 
Protocol Title:   
18F-FSPG PET/CT and Integrated Biomarkers for Early Lung Cancer Detection in Patients with 
Indeterminate Pulmonary Nodules 
 
 
 
 
 
 
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Expiration Date: October 24, 2024 
Participant ID: 
Adverse event monitoring will be performed as part of the procedures described 
above.  During the study period, the Study Doctors will monitor you for any potential 
side effects.  If the side effects are severe, the Study Doctors may temporarily stop 
study medication; change the dosage of your study medication; or withdraw your 
medication completely.  
If, at any time, you have any symptom; side effect; or injury affecting you physically or 
mentally during the study, you should tell the Study Doctors or nurses right away, 
even if you do not think it was caused by the study medication.  
If you have to go to the hospital for any reason, please tell the hospital staff that you are 
participating on a research study, and give them the contact information for the 
study team.  You may be provided with a card with the study team contact information. 
PARTICIPANT RESPONSIBILITIES  
As a participant, your responsibilities include:  
• Follow the instructions of the Protocol Director and study team.  
• Ask questions as you think of them.  
• Tell the Study Doctor or study team if you change your mind about staying in the 
study.  
• Tell the Study Doctor or study team about any side effects, doctor visits, or 
hospitalizations that you may have.  
• Tell the Study Doctor or study team if you believe you might be pregnant or gotten 
your partner pregnant.  
• Keep your study appointments.  If it is necessary to miss an appointment, please 
contact the Study Doctor or research study team to reschedule as soon as you know 
you will miss the appointment.  
About Pregnancy  
During the study, if you become pregnant, or you think you may be, you must tell your 
Study Doctor.  If you become pregnant during the study, the imaging agent may involve 
unforeseeable risks to the unborn baby, and your pregnancy will be followed to determine 
the outcome.  
WITHDRAWAL FROM THE STUDY 
 
If you first agree to participate and then you change your mind, you are free to 
withdraw your consent and discontinue your participation at any time.  Your decision will 
not affect your ability to receive medical care for your disease and you will not lose 
any benefits to which you would otherwise be entitled.  


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Carina Mari Aparici, MD 
IRB# 46607 
Protocol Title:   
18F-FSPG PET/CT and Integrated Biomarkers for Early Lung Cancer Detection in Patients with 
Indeterminate Pulmonary Nodules 
 
 
 
 
 
 
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Expiration Date: October 24, 2024 
Participant ID: 
If you decide to withdraw your consent to participate in this study, you should notify 
Dr Shaller at 650-725-5071 or Dr Aparici at 650-723-6855.   
 
POSSIBLE RISKS, DISCOMFORTS, AND INCONVENIENCES  
 
There are risks, discomforts, and inconveniences associated with any research study.  
This section describes the reasonably foreseeable risks, discomforts and inconveniences 
that you may experience.  In addition, because this is a research study, there may be 
risks that are not yet known (“unforeseeable”).  These deserve careful thought.  You 
should talk with the Study Doctor if you have any questions.  
You must tell the Study Doctor or study team about all side effects that you have.  If you 
are not honest about your side effects, it may not be safe for you to stay in the study.  
Your Study Doctor may give you medications to try to help lessen some of the side 
effects.  All patients in the study will be monitored for side effects.  
If you experience serious problems, you may be asked to return to the study center for 
more tests.  If you experience the following symptoms of an allergic reaction, contact the 
Study Doctor or the Study Team immediately.  
• Allergic reaction, including rash, hives, or blisters; increased heart rate (a fast pulse or 
tachycardia); or abnormal or increased sweating  
• Swelling of the face, mouth, lips, gums, tongue or neck 
• Wheezing or difficulty breathing  
• Dizziness and fainting  
Possible Side Effects Associated with the PET/CT Scans: 
• Radiologic imaging (PET/CT scans):  A PET/CT scan exposes you to radiation 
(discussed below).  When you are in the scanner, you may experience discomfort or 
anxiety due to be in the small space inside the machine, or from the loud noises the 
scanner makes.  If you become anxious or concerned in tight spaces, or from 
loud noises, tell the study team or technician before the scan.  You may receive a 
medication to calm you if you need help with this.  
• Injection of radiotracers (PET/CT scans):  Radiotracers (18F-FSPG and 18F-FDG) 
will be injected for the PET/CT scans. Following are the risks associated with 
injection of radiotracers.  
o Allergic reaction, which can include may include rash, hives, or blisters, and be 
severe and/or life-threatening.  If you have ever had a history of severe allergies 
/ allergic reactions, including anaphylaxis (eg, any bee-sting, food, shellfish, or 
nut reactions), or any previous reactions to medications; iodine; tape; or latex, 
tell the study team or technician before the scan.  After the injection and 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Carina Mari Aparici, MD 
IRB# 46607 
Protocol Title:   
18F-FSPG PET/CT and Integrated Biomarkers for Early Lung Cancer Detection in Patients with 
Indeterminate Pulmonary Nodules 
 
 
 
 
 
 
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Expiration Date: October 24, 2024 
Participant ID: 
during the scan, if you experience any breathing difficulties; sweating; numbness; 
or heart palpitations, tell the study team or technician immediately.  
o After the injection, there is a risk of pain, discomfort, or a burning sensation at the 
injection site; a flushing sensation; a salty or metallic taste in the mouth; a brief 
headache; or nausea/vomiting.  These effects usually last for a few moments.  
Pain, discomfort, or a burning sensation at the injection site can usually be 
relieved by applying moist, warm compresses to the injection site.  
• Radiation from PET/CT scans:  You will be exposed to radiation during this research 
from 1 F18-FDG PET/CT and 1 F18-FSPG PET/CT scans. Your radiation exposure 
will be about 21.5 mSv.  The additional amount of radiation exposure is approximately 
equal to 43% of the limit that radiation workers (for example, a hospital x-ray 
technician) are allowed to receive in one year. This additional amount of radiation 
involves minimal risk and is necessary to obtain the research information desired. 
Due to the risk of injury to the developing baby (fetus) from radionuclide 
angiography, you should notify your physician if you are pregnant, or suspect that 
you may be pregnant.  Radiation exposure during pregnancy may lead to birth 
defects.  If you are lactating, or breastfeeding, you should notify your physician due 
to the risk of contaminating breast milk with the radionuclide.  
• Allergic reactions:  All drugs and imaging agents have a potential risk of an allergic 
reaction, which if not treated promptly, could become life-threatening.  You should 
get medical help and contact the Study Doctors right away if you think you have any 
of the following symptoms of a serious allergic reaction:  trouble breathing, or 
swelling of the face, mouth, lips, gums, tongue or neck.  Other allergic reactions may 
include rash, hives, or blisters.  
Other procedural risks: 
• Nasal brushing:  Nasal brushing may be accompanied by minor discomfort and a 
slight chance of temporary nose bleed. 
• Blood draws:  A blood draw may cause fainting;  inflammation of the vein;  stinging, 
discomfort, or pain;  bruising;  discomfort;  redness;  burning;  or bleeding at the site 
where the needle is placed to draw the blood.  There is a slight chance of infection.  
You may feel dizzy or you may faint.  If you feel faint, you should immediately lie 
down to avoid falling.  
• IV catheters:  IV catheters may be accompanied by mild bruising and, in some cases, 
by swelling, redness, injection site pain and infection. 
• Genetic research risks:  This research involves genetic studies and information.  
Procedures have been put into place that are designed to make it very difficult for 
the results from genetic research to be linked to you.  However, even without your 
name or other identifiers, your genetic information is unique to you, and there is a 
remote possibility that someone could trace the information in a central database 
back, and identify you.  If a genetic disorder is discovered in your genes, there is a 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Carina Mari Aparici, MD 
IRB# 46607 
Protocol Title:   
18F-FSPG PET/CT and Integrated Biomarkers for Early Lung Cancer Detection in Patients with 
Indeterminate Pulmonary Nodules 
 
 
 
 
 
 
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Expiration Date: October 24, 2024 
Participant ID: 
remote possibility this information could become public and affect you or your family 
in an unfavorable way, including a possible risk of discrimination by employers or 
insurance providers.  
• Personal anxiety:  Following are some common concerns that research subjects 
may have.  
o You may be asked sensitive or private questions which you normally do not 
discuss.  It may be necessary to answer some of these questions related to your 
health and medical status.  
o You may feel embarrassed during the physical exam.  You may request that the 
physical exam be done by a clinician of the same gender.  
o You may be concerned about your personal information being revealed.  
Although the Study Team, FDA;  and the funding sources (The Canary 
Foundation, the American Association for Cancer Research, and Department of 
Defense) do their best to protect your personal information, this can not be 
absolutely guaranteed.  
• Test results:   
o May indicate that you have another disease or condition that you were not aware 
of.  This may be concerning to you, and cause anxiety or other feelings. 
o Rarely, may not be correct.   
 A false negative is a test result that indicate a person does not have a 
condition, but they really do. 
 A false positive is a test result that indicates a person has a condition, but 
they really don’t. 
 Incorrect results can cause as much concern and anxiety as a correct diagnosis.  
o May become known to others, which may affect their judgment of you.   
• Pregnancy / Reproductive Risk:  There is a risk that pregnancy could still result 
despite the responsible use of reliable method of birth control.   
• Other risks:  Since 18F-FSPGis investigational (“experimental”), there may be other 
risks that are unknown (“unforeseeable”) at this time.  
It is important that you report all symptoms and side effects that you experience 
as soon as they occur, whether or not you think they are caused by the 
imaging agent 18F-FSPG or study procedures.  Contact Dr Shaller at 650-725-5071;  
Dr Aparici at 650-723-6855;  or the Nurse Coordinators at 650-498-6000 (24 hours).  
If you are unable to reach anyone at the number(s) listed above, and you feel you may 
need medical attention, call 911 or go to the nearest emergency room.  


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Carina Mari Aparici, MD 
IRB# 46607 
Protocol Title:   
18F-FSPG PET/CT and Integrated Biomarkers for Early Lung Cancer Detection in Patients with 
Indeterminate Pulmonary Nodules 
 
 
 
 
 
 
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Participant ID: 
POTENTIAL BENEFITS  
• The diagnostic testing with 18F-FSPG may result in a better understanding of your 
medical condition, which may lead to better treatment choices.  However, there is no 
guarantee that you will benefit in this or any other way.  
• Although you may not directly benefit from participation in this study, information 
learned from this study may help other people in the future, including other people 
with cancer.  
We cannot and do not guarantee or promise that you will receive any benefits from this 
study.  
ALTERNATIVES 
You do not have to be in this study to receive a medical scan to evaluate your lung 
nodules of unknown cause.  You may choose to not participate, and receive a PET/CT 
scan with 18F-FDG only, or receive a different medical scan altogether. 
The Study Doctors will discuss with you the risks and benefits of the alternatives, 
including which other choices might be suitable for you.  
If you decide that you do not wish to take part in this study and wish to pursue any of 
these, or other alternatives, this will not change your regular medical care or the other 
treatment choices in any way.  
PARTICIPANT’S RIGHTS 
You should not feel obligated to agree to participate.  Your questions should be answered 
clearly and to your satisfaction.  If you decide not to participate, tell the Protocol Director.  
You can also tell any other member of the study team. 
You will be told of any significant new information that is learned during the course of this 
research study, which might affect your condition or your willingness to continue 
participation in this study.  After you hear about this information, you have the right to 
withdraw from the program.  
If medically-relevant information about you or your test results that might affect your 
future treatment or your willingness to continue participation in this study is obtained, this 
information will be discussed with you.  
You will be told the results of tests that are part of your medical care, but you may not 
be told the results of the research tests, including any future research tests.  


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Carina Mari Aparici, MD 
IRB# 46607 
Protocol Title:   
18F-FSPG PET/CT and Integrated Biomarkers for Early Lung Cancer Detection in Patients with 
Indeterminate Pulmonary Nodules 
 
 
 
 
 
 
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Expiration Date: October 24, 2024 
Participant ID: 
ClinicalTrials.gov 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by US Law.  This web site will not include information that can identify you.  
At most, the web site will include a summary of the results.  You can search this 
web site at any time.  
CONFIDENTIALITY 
The results of this research study may be presented at scientific or medical meetings or 
published in scientific journals.  Your identity and/or your personal health information will 
not be disclosed except as authorized by you or as required by law.  However, there is 
always some risk that even de-identified information might be re-identified.  
Your research records may be disclosed outside of Stanford, including in computer 
databases and by other electronic methods, but you will only be identified by your unique 
study identifier, and not your name.  Information linking your study identifier to your name 
will be kept in a secure location at Stanford and access will be limited to the Study Doctor 
and authorized members of the Study Team.  
Patient information may be provided to Federal and other regulatory agencies 
as required.  The US FDA, for example, may inspect research records and learn your 
identity if this study falls within its jurisdiction.  
Representatives of the Department of Defense may have access to the research records. 
The purpose of this research study is to obtain data or information on the safety and 
effectiveness of 18F-FSPG;  the results will be provided to the Food and Drug 
Administration (FDA);  other federal and regulatory agencies as required; and the funding 
sources (The Canary Foundation, the Department of Defense and the American 
Association for Cancer Research).  


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Carina Mari Aparici, MD 
IRB# 46607 
Protocol Title:   
18F-FSPG PET/CT and Integrated Biomarkers for Early Lung Cancer Detection in Patients with 
Indeterminate Pulmonary Nodules 
 
 
 
 
 
 
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Expiration Date: October 24, 2024 
Participant ID: 
Authorization To Use Your Health Information  
For Research Purposes 
Because information about you and your health is personal and private, it generally 
cannot be used in this research study without your written authorization.  If you 
sign this form, it will provide that authorization.  The form is intended to inform 
you about how your health information will be used or disclosed in the study.  
Your information will only be used in accordance with this authorization form and 
the informed consent form and as required or allowed by law.  Please read it 
carefully before signing it.  
 
What is the purpose of this research study and how will my health 
information be utilized in the study?  
This study may help the study team;  the funding sources (The Canary Foundation 
and the American Association for Cancer Research);  and FDA evaluate the utility 
of 18F-FSPG as an PET/CT imaging agent.  Information from this study will be 
submitted to the funding source and international regulatory agencies including the 
FDA.  The results from this research study are expected to be presented at 
scientific or medical meetings or published in scientific journals.  You will not be 
personally identified in the publications, although representatives of the 
sponsor and FDA and other international regulatory agencies may need to 
know who you are.  
 
Do I have to sign this authorization form? 
You do not have to sign this authorization form.  But if you do not, you will not be 
able to participate in this research including receiving any research-related 
treatment.  Signing the form is not a condition for receiving any medical care 
outside the study.  
 
If I sign, can I revoke it or withdraw from the research later?  
If you decide to participate, you are free to withdraw your authorization regarding 
the use and disclosure of your health information (and to discontinue any other 
participation in the study) at any time.  After any revocation, your health 
information will no longer be used or disclosed in the study, except to the extent 
that the law allows us to continue using your information (eg, necessary to 
maintain integrity of research).  If you wish to revoke your authorization for the 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Carina Mari Aparici, MD 
IRB# 46607 
Protocol Title:   
18F-FSPG PET/CT and Integrated Biomarkers for Early Lung Cancer Detection in Patients with 
Indeterminate Pulmonary Nodules 
 
 
 
 
 
 
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Aparici--Bedi / IRB-46607 ICF_13 June 2022 
IRB Use Only 
Approval Date:   October 24, 2023 
Expiration Date: October 24, 2024 
Participant ID: 
research use or disclosure of your health information in this study, you must write 
to:  
Carina Mari Aparici, MD  
300 Pasteur Dr, H2200 
Stanford Univ Med Center;  MC 5281 
Stanford, CA  94305-5427 
 
What Personal Information Will Be Obtained, Used or Disclosed?  
Your health information related to this study, may be used or disclosed in 
connection with this research study, including, but not limited to identifiers such as 
your name and initials;  address including ZIP code;  phone numbers;  dates 
including date of birth;  age;  biological gender (your sex);  race;  ethnicity;  
Social Security Number;  medical record number (MRN);  and other numbers or 
codes such as your unique study identifier that might identify you.  During the 
study, researchers will also obtain information about your health status, life-style 
choices, medical history, and medical diagnoses, including family medical history 
and allergies;  your current and past medications or therapies;  your laboratory 
test results including blood and pregnancy tests;  results of procedures, such as 
medical measurements or assessments, medical scans including PET/CT scans, 
results of genetic testing;  and medical reports, such as radiology reports.  The 
researchers will also get information from your medical record (including 
hospital records from the Stanford Healthcare and your referring 
physician’s records).  
 
Who May Use or Disclose the Information?  
The following parties are authorized to use and/or disclose your health information 
in connection with this research study:  
• The Protocol Director Carina Mari Aparici, MD  
• Research Staff 
• The Stanford University Administrative Panel on Human Subjects in Medical 
Research 
 
Who May Receive or Use the Information? 
The parties listed in the preceding paragraph may disclose your health information 
to the following persons and organizations for their use in connection with this 
research study:  


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Carina Mari Aparici, MD 
IRB# 46607 
Protocol Title:   
18F-FSPG PET/CT and Integrated Biomarkers for Early Lung Cancer Detection in Patients with 
Indeterminate Pulmonary Nodules 
 
 
 
 
 
 
Page 15 of 19 
 
Aparici--Bedi / IRB-46607 ICF_13 June 2022 
IRB Use Only 
Approval Date:   October 24, 2023 
Expiration Date: October 24, 2024 
Participant ID: 
• The Stanford Data and Safety Monitoring Committee (DSMC);  and/or any other 
unit of Stanford University as necessary 
• The funding sources (The Canary Foundation and the American Association for 
Cancer Research, Department of Defense);  or their representatives  
• The Food and Drug Administration (FDA) and/or other state or international 
regulatory authorities  
• The Office for Human Research Protections (OHRP) in the US Department of 
Health and Human Services (DHHS) 
 
Your information may be re-disclosed by the recipients described above, if they are 
not required by law to protect the privacy of the information.  
 
When will my authorization expire? 
Your authorization for the use and/or disclosure of your health information will 
end on 31 December 2068 or when the research project ends, whichever is earlier.  
 
Will access to my medical record be limited during the study? 
To maintain the integrity of this research study, you may not have access to any 
health information developed as part of this study until it is completed.  At that 
point, you would have access to such health information if it was used to make a 
medical or billing decision about you (eg, if included in your official medical 
record).  
___________________________________________ 
Printed Name of Adult Participant  
 
___________________________________________ 
____________  
Signature of Adult Participant  
 
 Date 
 
NOTE:  If using the Short Form Consent process for informed consent in another 
language pursuant to an "Alteration of HIPAA Authorization," neither the 
participant nor their LAR should sign the HIPAA “Authorization To Use Your 
Health Information For Research Purposes” above.  


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Carina Mari Aparici, MD 
IRB# 46607 
Protocol Title:   
18F-FSPG PET/CT and Integrated Biomarkers for Early Lung Cancer Detection in Patients with 
Indeterminate Pulmonary Nodules 
 
 
 
 
 
 
Page 16 of 19 
 
Aparici--Bedi / IRB-46607 ICF_13 June 2022 
IRB Use Only 
Approval Date:   October 24, 2023 
Expiration Date: October 24, 2024 
Participant ID: 
FINANCIAL CONSIDERATIONS 
Costs 
If you participate in this study, the study will pay for those services, supplies, procedures, 
and care associated with this study that are not a part of your routine medical care.  
However, there may be additional costs to you.  These include basic expenses like 
transportation and the personal time it will take to come to the Study Visits.   
You and/or your health insurance must pay for services, supplies, procedures, and care 
that are required during this study for routine medical care.  You will also be 
responsible for any co-payments and/or deductibles as required by your 
insurance.  Participation in this study is not a substitute for health insurance.   
Some insurance companies or other 3rd-party payers may not pay for standard-of-care 
procedures or laboratory tests, including hospitalization, when they are done as part of a 
research study.  You should consult with your health benefit plan to determine whether 
your medical costs associated with your care during this study are covered.  
Payments  
Compensation for study participation may be available in the amount of up to $500.  
Participants who complete the second PET scan are eligible for this compensation.  The 
study team will provide more information on compensation.  
Payments or reimbursement may only be made to US citizens, legal resident aliens, and 
those who have a work-eligible visa.  You may need to provide your Social Security 
Number (SSN) or equivalent (ie, federal Taxpayer Identification Number, TIN) to receive 
payment.  If your SSN/ TIN is required to receive payment, and you do not wish to provide 
your SSN/ TIN, you have the option of declining the payment.  
This study includes the collection of research samples.  Any of your samples which are 
used in research, including those used in genetic research, may result in new products; 
tests;  or discoveries.  In some instances, these products may have commercial value, 
and may be developed and owned by the study team; Stanford University;  the funding 
sources (The Canary Foundation and the American Association for Cancer Research, 
Department of Defense) and/or others.  However, donors of samples do not retain any 
property rights to the samples or data derived from them.  Therefore, you would not share 
in any financial benefits from these products, tests or discoveries.  
Any of your samples which are used in research may result in new products, tests or 
discoveries.  In some instances, these may have potential commercial value and may be 
developed and owned by the study team; Stanford University; and/or others.  However, 
donors of samples do not retain any property rights to the materials.  Therefore, you 
would not share in any financial benefits from these products, tests or discoveries.  
 
 
 
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Carina Mari Aparici, MD 
IRB# 46607 
Protocol Title:   
18F-FSPG PET/CT and Integrated Biomarkers for Early Lung Cancer Detection in Patients with 
Indeterminate Pulmonary Nodules 
 
 
 
 
 
 
Page 17 of 19 
 
Aparici--Bedi / IRB-46607 ICF_13 June 2022 
IRB Use Only 
Approval Date:   October 24, 2023 
Expiration Date: October 24, 2024 
Participant ID: 
Funding Source  
The Canary Foundation, a non-profit entity involved in early cancer detection and the 
Department of Defense are paying for (sponsoring) this study. 
 
COMPENSATION for Research-Related Injury 
 
All forms of medical diagnosis and treatment – whether routine or experimental – 
involve some risk of injury.  In spite of all precautions, you might develop 
medical complications from participating in this study.  If such complications arise, the 
Protocol Director and the research study team will assist you in obtaining appropriate 
medical treatment.  In the event that you have an injury or illness that is directly caused 
by your participation in this study, reimbursement for all related costs of care first will be 
sought from your insurer, managed care plan, or other benefits program.  You will be 
responsible for any associated co-payments or deductibles as required by 
your insurance.  
If costs of care related to such an injury are not covered by your insurer, 
managed care plan or other benefits program, you may be responsible for these costs.  
If you are unable to pay for such costs, the Protocol Director and/or the research 
study staff will assist you in applying for supplemental benefits and explain how to apply 
for patient financial assistance from the hospital.  
You do not waive any liability rights for personal injury by signing this form. 
 
CONTACT INFORMATION  
 
Questions, Concerns, Complaints, or to Report an Injury or Side Effect:  If you 
have any questions, concerns or complaints about this research study, its procedures, 
risks and benefits, or alternative courses of treatment, you should contact the 
Study Doctor, Brian Shaller, MD, at 650-725-5071, or Dr Aparici at 650-723-6855.  You 
should also contact them at any time if you feel you have been hurt by being a part of 
this study.  
If you are unable to reach anyone at the number(s) listed above, and you feel you may 
need medical attention, call or go to the nearest emergency room.  
Independent Contact:  If you are not satisfied with how this study is being conducted, 
or if you have any concerns, complaints, or general questions about the research or 
your rights as a participant, please contact the Stanford Institutional Review Board (IRB) 
to speak to someone independent of the research team at 650-723-5244 or toll-free at 
1-866-680-2906.  You can also write to the Stanford IRB, Stanford University, 
1705 El Camino Real, Palo Alto, CA 94306. 
Alternate Contact:  If you cannot reach the Study Doctor, please contact Dr Aparici at 
650-723-6855. 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Carina Mari Aparici, MD 
IRB# 46607 
Protocol Title:   
18F-FSPG PET/CT and Integrated Biomarkers for Early Lung Cancer Detection in Patients with 
Indeterminate Pulmonary Nodules 
 
 
 
 
 
 
Page 18 of 19 
 
Aparici--Bedi / IRB-46607 ICF_13 June 2022 
IRB Use Only 
Approval Date:   October 24, 2023 
Expiration Date: October 24, 2024 
Participant ID: 
Appointment Contact:  If you need to change your appointment, please contact 
Dr Shaller at 650-725-5071 or Dr Aparici at 650-723-6855. 
 
EXPERIMENTAL SUBJECT’S BILL OF RIGHTS 
As a research participant you have the following rights.  These rights include but are 
not limited to the participant's right to:  
• 
Be informed of the nature and purpose of the experiment;  
• 
Be given an explanation of the procedures to be followed in the 
medical experiment, and any drug or device to be utilized;  
• 
Be given a description of any attendant discomforts and risks reasonably 
expected;  
• 
Be given an explanation of any benefits to the subject reasonably to be expected, 
if applicable;  
• 
Be given a disclosure of any appropriate alternatives, drugs or devices that might 
be advantageous to the subject, their relative risks and benefits;  
• 
Be informed of the avenues of medical treatment, if any available to the subject 
after the experiment if complications should arise;  
• 
Be given an opportunity to ask questions concerning the experiment or the 
procedures involved;  
• 
Be instructed that consent to participate in the medical experiment may be 
withdrawn at any time and the subject may discontinue participation without 
prejudice;  
• 
Be given a copy of the signed and dated consent form; and  
• 
Be given the opportunity to decide to consent or not to consent to a medical 
experiment without the intervention of any element of force, fraud, deceit, duress, 
coercion or undue influence on the subject's decision.  


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Carina Mari Aparici, MD 
IRB# 46607 
Protocol Title:   
18F-FSPG PET/CT and Integrated Biomarkers for Early Lung Cancer Detection in Patients with 
Indeterminate Pulmonary Nodules 
 
 
 
 
 
 
Page 19 of 19 
 
Aparici--Bedi / IRB-46607 ICF_13 June 2022 
IRB Use Only 
Approval Date:   October 24, 2023 
Expiration Date: October 24, 2024 
Participant ID: 
May we contact you about future studies that may be of interest to you? ___Yes ___No  
Signing your name means you agree to be in this study and that you will receive a copy 
of this signed and dated consent form.  
 
_______________________________________________ 
Printed Name of Adult Participant 
  
_______________________________________________ 
____________  
Signature of Adult Participant 
 Date 
_______________________________________________ 
Printed Name of Person Obtaining Consent (POC) 
 
_______________________________________________ 
____________  
Signature of POC  
 Date 
 
 
 
The following witness line is to be signed only if the consent is provided as a summary form and 
accompanied by a short-form foreign language informed consent document. 
 
_______________________________________________ 
____________  
Signature of Witness 
 Date 
(eg, staff, translator/interpreter or family member)  
 
________________________________________________________ 
Print Name of Witness 
The translated short form must be signed and dated by BOTH the participant AND the witness.  
The English consent form (“referred to as the "Summary Form" in the regulations”):  
Must be signed by BOTH the witness AND the Person Obtaining Consent (POC).  
The non-English speaking participant does NOT sign the English consent.  
The non-English speaking participant should NOT sign the HIPAA participant line.  
If the participant is non-English speaking, the POC must ensure that:  
 
Any questions or options presented by the consent form are documented and initialed by the  
     POC on the Summary Form, per the participant's wishes, as they are understood during the  
     consent process. .