Clinical trial NCT04365660
Conditions: Osteosarcoma
Sponsor: Davidzon, Guido, M.D.
Start date: 2021-01-28; Completion date: 2021-07-22
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this research is to evaluate the study drug, 18F FTC-146, as a positron emission tomography (PET) / computed tomography (CT) radiotracer imaging agent to evaluate tumor status in patients newly diagnosed with osteosarcoma ("bone cancer").

Detailed description:
Primary Objective: Demonstrate correlation of pre-post reduction in 18F-FTC-146 PET/CT with amount of post-treatment tumor necrosis in newly-diagnosed and treated osteosarcoma patients.

Secondary Objective: Demonstrate correlation of pre-post reduction in 18F-FTC-146 PET/CT with amount of post-treatment pain reduction in newly-diagnosed and treated osteosarcoma patients.

Arms: arm 1: For PET scans, subjects will receive intravenous injection of 10 mCi 18-F -FTC 146 administered twice with 18-F-FTC 146, once at baseline (pre chemotherapy) and once at final study visit (post chemotherapy).
Interventions: intervention 1: 18-F FTC 146
Intervention descriptions: intervention 1: Radiotracer, 10 mCi at pre- and post- chemotherapy, intravenous administration

Protocol documents:
Prot_SAP_001.pdf: 
IRB-52746 
29 March 2021 
Page 1 of 23 
CONFIDENTIAL 
Stanford Cancer Institute 
A Phase 2 Study of 18F-FTC-146 PET/CT in 
Patients with Newly-Diagnosed 
Osteosarcoma 
Protocol Director  
Kristen Ganjoo, MD 
Stanford University 
875 Blake Wilbur Drive,
 
Stanford, CA 94305 
Phone:  
 
Fax:  
 
Email:  kganjoo@stanford.edu 
Sub-Investigators 
Frederick T Chin, PhD 
1201 Welch Road, 
 
Stanford, CA 94305-5484 
Phone:  
 
Fax:  
 
  
Nam Bui, MD 
 
Stanford, CA 94395 
Phone:  
;  
Fax 
 
 
  
Guido Alejandro Davidzon, MD 
Nuclear Medicine, 
300 Pasteur Drive,
 
Phone:  
 
  
Biostatistician 
, PhD 
1201 Welch Road, 
 
Stanford, CA 94305-5488 
Phone:  
 
Fax:  
 
 
Study Coordinator 
 
800 Welch Rd 
 
Palo Alto, CA 94304 
Phone:  
  
Fax:  
 
 
 
IRB-52746 
SARCOMA0041 
NCT04365660 
IND 
 
Version 4, 29 March 2021 
(initial) SRC Approval Date:  30 January 2020 


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CONFIDENTIAL 
 
PROTOCOL HISTORY TABLE 
 
Version 
no. 
Version  
Date 
Summary or Rationale (brief, following are example changes) 
1 
16 January 2020 Initial SRC approved protocol on 30 January 2020  
2 
12 February 2020 1. Minor corrections on doses of 18F-FTC-146 
  
3 
27 October 2020 
1. Add +/- 20% to dose of 18F-FTC-146.   
2. Add information on limited dynamic PET emission scan:  A low dose 
CT will be obtained from vertex to toes; this will use 120 kV and dose 
modulation based on body habitus, ranging 10 to 105  mA.  This will be 
followed by 30 to 60-minute limited dynamic PET emission scan in a 
region of interest of known osteosarcoma (a 30-minute scan will be 
obtained for most patients; this may be extended for up to 60 minutes 
in 1 to 2 patients).  Immediately after the limited dynamic scan, a static 
whole-body PET emission scan will be acquired (approximately 
25 minutes). 
3. NCT number added 
4 
15 March 2021 
 
Defines that only AEs and SAEs related to PET/CT procedure will be 
collected and recorded.  Related adverse events will be recorded from 
the time the subject signs informed consent and for 30 days from the 
time of the last investigational scan.  SAEs will be tracked until 
resolution and 30 days after the last investigational scan.  
 
Inserted Section 4.1 “Treatment / Procedure Plan,” to provide 
information on screening assessments, enrollment, study procedures, 
and completion of participation.  Subsequent section re-numbered.  
 
Study calendar updated.  
 
Defines that the PROMIS questionnaire may be completed within 
2 weeks prior to investigational scans. 
 
Defines that a subject’ participation in the study is complete once the 
final investigational scan;  the PROMIS questionnaire;  and pathology 
report has been collected. 
 
Adds field for unique subject identifier and standard study identifier 
fields to the Inclusion/Exclusion Criteria Checklist (Appendix A).  Also 
adds 2 additional signature lines for a total of 3 signature lines for 
eligibility triple check.  
5 
29 March 2021 
 
Removes Exclusion Criteria regarding biopsy-proven osteosarcoma 
that was reviously added in error.  


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CONFIDENTIAL 
TABLE OF CONTENTS 
 
PROTOCOL HISTORY TABLE ............................................................................................. 2 
PROTOCOL SYNOPSIS ........................................................................................................ 5 
SCHEMA ............................................................................................................................... 6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS (Example) ................................ 7 
1. 
OBJECTIVES ................................................................................................................. 9 
1.1. 
Primary Objective ..................................................................................................... 9 
1.2. 
Secondary Objective ................................................................................................ 9 
2. 
BACKGROUND ............................................................................................................. 9 
2.1. 
Study Disease ........................................................................................................... 9 
2.2. 
Study Agent/Device/Imaging Procedure ................................................................. 9 
2.3. 
Clinicaltrials.gov ......................................................................................................10 
2.3.1. 
Clinicaltrials.gov Outcomes ................................................................................10 
2.3.1.1  Primary Outcome (Outcome 1) ......................................................................................... 10 
2.3.1.2  Secondary Outcomes ....................................................................................................... 11 
2.4. 
Rationale ..................................................................................................................11 
2.5. 
Preliminary results ..................................................................................................11 
2.6. 
Study Design............................................................................................................12 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES .............................12 
3.1. 
Inclusion Criteria .....................................................................................................12 
3.2. 
Exclusion Criteria ....................................................................................................12 
3.3. 
Informed Consent Process .....................................................................................12 
3.4. 
Study Timeline .........................................................................................................12 
3.4.1. 
Primary Completion:............................................................................................12 
4. 
IMAGING AGENT/DEVICE/PROCEDURE INFORMATION ..........................................13 
4.1. 
Treatment / Procedure Plan ....................................................................................13 
4.2. 
PET/CT Scan ............................................................................................................14 
5. 
STUDY PROCEDURES ................................................................................................15 
5.1. 
Criteria for Removal from Study .............................................................................15 
6. 
STUDY CALENDAR .....................................................................................................16 


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7. 
ADVERSE EVENTS AND REPORTING PROCEDURES .............................................16 
7.1. 
Potential Adverse Events ........................................................................................16 
7.2. 
Adverse Event Reporting ........................................................................................17 
8. 
REGULATORY CONSIDERATIONS ............................................................................17 
8.1. 
Institutional Review of Protocol .............................................................................17 
8.2. 
Data Management Plan ...........................................................................................17 
8.3. 
Data and Safety Monitoring Plan ............................................................................17 
9. 
MEASUREMENTS ........................................................................................................18 
9.1. 
Primary and Secondary Endpoints ........................................................................18 
9.2. 
Measurement Methods ............................................................................................18 
9.3. 
Measurement Time Points ......................................................................................18 
10. 
STATISTICAL CONSIDERATIONS ..........................................................................18 
10.1. 
Statistical Design .....................................................................................................18 
10.2. 
Descriptive Statistics and Exploratory Data Analysis ..........................................18 
10.3. 
Primary Analysis .....................................................................................................19 
10.3.1. 
Analysis Population.............................................................................................19 
10.3.2. 
Analysis Plan .....................................................................................................19 
10.4. 
Secondary Analysis .................................................................................................19 
10.4.1. 
Analysis Population ............................................................................................19 
10.4.2. 
Analysis Plan .....................................................................................................19 
10.5. 
Sample Size .............................................................................................................19 
10.6. 
Accrual estimates ....................................................................................................19 
10.7. 
Criteria for future studies ........................................................................................19 
11. 
REFERENCES ..........................................................................................................20 
Appendix A ..............................................................................................................................21 
Appendix B: .............................................................................................................................23 
 


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PROTOCOL SYNOPSIS 
TITLE 
A Phase 2 Study of 18F-FTC-146 PET/CT in Patients with Newly-Diagnosed 
Osteosarcoma  
STUDY PHASE 
Phase 2  
INDICATION 
Tumor imaging  
INVESTIGATIONAL 
PRODUCT  
18F-FTC-146  
PRIMARY 
OBJECTIVE(S) 
Demonstrate correlation of pre-post reduction in 18F-FTC-146 PET/CT with 
amount of post-treatment tumor necrosis in newly-diagnosed and treated 
osteosarcoma patients.  
SECONDARY 
OBJECTIVE(S) 
Demonstrate correlation of pre-post reduction in 18F-FTC-146 PET/CT with 
amount of post-treatment pain reduction in newly-diagnosed and treated 
osteosarcoma patients. 
TREATMENT 
SUMMARY 
Participants will be assessed with 18F-FTC-146 PET/CT imaging at baseline 
and after neoadjuvant (pre-surgery) chemotherapy but before surgery itself. 
SAMPLE SIZE  
5 
STATISTICAL 
CONSIDERATIONS 
Descriptive statistics and correlations will be calculated.  
Means, medians, and standard deviations of: 
1. Histologically determined percentage of necrosis in post-
chemotherapy resected tumor. 
2. Pre- and post-treatment SUVmax in tumor ROI, and the pre-post 
percent change. 
3. Pre- and post-treatment pain score, and the pre-post difference. 
Primary Analysis  
1.  The following will be recorded for each patient 
(a) the histological percentage of necrosis and 
(b) the percent reduction in SUVmax. 
2.  The histological percent necrosis will be plotted against SUVmax 
percent reduction to calculate rank correlation. 
Secondary Analysis 
1.  The following will be recorded for each patient 
(a) the post-treatment reduction in pain score  
(b) the percent reduction in SUVmax  
2.  The reduction in pain score will be plotted against SUVmax reduction to 
calculate rank correlation. 
Sample Size 
Preliminary approval for this study is for 5 subjects only.  An eventual 
sample size of 20 will provide 90% power at one-sided 5% error to detect 
a correlation as low as 0.60.   


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CONFIDENTIAL
SCHEMA
Patient Consent
Baseline PET/CT Imaging (Pre-chemo)
Neoadjuvant Chemotherapy  
Final Visit PET/CT (Post-chemo)
Surgical resection of tumor (Standard of care)


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CONFIDENTIAL 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS (Example) 
CBC 
Complete blood count 
CI 
Confidence interval 
CMAX 
Maximum concentration of drug 
CNS 
Central nervous system 
CRF 
Case report/Record form 
CR 
Complete response 
CSM 
Conventional Staging Method 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
ECOG Performance Status 
Easter Cooperative Oncology Group Performance Status 
EFS 
Event Free Survival 
FDG 
Fluorodeoxyglucose 
GI 
Gastrointestinal 
Hgb 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
HPF 
High-power field  
HTN 
Hypertensions 
IPI 
International Prognostic Index 
IRB 
Institutional Review Board 
IV 
Intravenous 
LLN 
Lower limit of normal  
NHL 
Non-Hodgkin’s Lymphoma 
NPV 
Negative Predictive Value 
OS 
Overall survival  
PET/CT 
Positron emission tomography – computed tomography 
PLT 
Platelet 
PD 
Progressive diseased 
PPV 
Positive Predictive Value 
PFS 
Progression free survival  
PR 
Partial response 
QD 
Once daily 
RECIST 
Response evaluation criteria in solid tumors 
RM 
Residual Mass 


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CONFIDENTIAL 
ROC 
Receiver-Operative-Characteristic 
RR 
Response rate 
S1R 
Sigma-1 receptor 
SAE 
Serious adverse event 
SD 
Stable disease 
SUV 
Standard Uptake Value 
TTP 
Time to progression 
ULN 
Upper limit of normal 
UNK 
Unknown 
WBC 
White blood cell 
WHO 
World Health Organization 


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CONFIDENTIAL 
 
1. OBJECTIVES 
1.1. Primary Objective 
 
Demonstrate correlation of pre-post reduction in 18F-FTC-146 PET/CT with amount of 
post-treatment tumor necrosis in newly-diagnosed and treated osteosarcoma patients.   
1.2. Secondary Objective 
 
Demonstrate correlation of pre-post reduction in 18F-FTC-146 PET/CT with amount of 
post-treatment pain reduction in newly-diagnosed and treated osteosarcoma patients. 
2. BACKGROUND 
2.1. Study Disease 
Osteosarcomas are the most common bone sarcomas in adults.  Patients with localized 
disease are curable with neoadjuvant chemotherapy followed by surgical resection.  The 
single most important prognostic factor is the percent necrosis in the post-chemotherapy 
resected specimen.  Patients with tumors > 90% necrosis have an excellent long-term 
survivals.  However, patients with < 90% necrosis have a poor prognosis with early signs of 
disease recurrence with metastatic spread.   
2.2. Study Agent/Device/Imaging Procedure 
Fredrick Chin, PhD, has developed a novel sigma-1 receptor (S1R) imaging probe, 
18F-FTC-146, that is highly-selective for targeting S1R expressed in brain.  S1Rs are widely 
distributed throughout the brain where they interact with ion channels and neurotransmitters 
involved in learning, memory, and the development of compulsive behavior.  The proposed 
research is technically innovative because of its use of 18F-FTC-146, the only 
known tracer that does not suffer from off-target binding and in vivo instability, for S1Rs.  
The S1R targeting specificity of 18F-FTC-146 has already been studied in rodents, monkeys, 
and more recently in humans.  With the departmental support provided by 
Dr Sanjiv Sam Gambhir (Chair, Department of Radiology), Dr Chin, in collaboration 
Sanjiv Sam Gambhir, MD, first obtained an Exploratory Investigational New Drug Application 
(IND 126459) to use 18F-FTC-146 in first-in-human studies, and have previously converted 
the exploratory IND to a full IND (IND 
) .  
Since Dr Chin has shown that 18F-FTC-146 has excellent affinity to S1R (> 100,000-fold 
higher than any other receptor targets in the brain including S2R) and the lipophilicity of this 
ligand (logD pbs7.4 = 1.45) falls in an ideal range for the Blood Brain Barrier, these 
favorable properties allow 18F-FTC-146 to be a promising candidate for selective PET 
S1R-neuroimaging.  He has made 18F-FTC-146 and knows its biodistribution and 
pharmacokinetics in mice.  The radiotracer displays good distribution volume (~2.4) and 
excellent S1R-specificity and selectivity in WT vs S1R knockout (KO) mice.  S1R expression 
level strongly correlated with 18F-FTC-146 autoradiography signal in brain regions with high 
S1R expression when compared with immunohistochemical staining.  To determine 


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CONFIDENTIAL 
test-retest variability of brain uptake (%ID/g), 3 healthy mice were injected with 18F-FTC-146 
with a 7-day interval between measurements, and results ranged from 10 to 17% in 10 brain 
regions.  In rat biodistribution studies, 18F-FTC-146 demonstrated specific uptake in S1R 
rich rat organs, including the lungs, pancreas, spleen, and brain.  Preliminary monkey 
PET/MRI studies revealed similar 18F-FTC-146 accumulation in brain (mainly in cortical 
structures, cerebellum, and vermis) that could be attenuated by pretreatment with S1R 
agonist haloperidol.  In addition, he also performed supporting dosimetry and toxicity studies 
in rodents for clinical translation.  An Exploratory Investigational New Drug (eIND) 
Application for 18F-FTC-146 was submitted to the Food and Drug Administration (FDA) for 
first-in-human studies to examine radiotracer biodistribution and pharmacokinetics and 
first-in-human studies in typically developing volunteers (N = 10) and patients with pain 
(N = 30) were performed by his group.  His initial evaluation of 18F-FTC-146 in humans 
shows that this radiotracer is safe and the adsorbed radiation doses measured are 
acceptable to be used for other indications including OCD, HD, and other 
neurodegenerative diseases.  More recently, eIND 126459 was converted to full 
IND 
(activated 9 May 2018). 
2.3. Clinicaltrials.gov 
This study of 18F-FTC-146 for PET/CT imaging is investigational, and has been submitted to 
IND 
. 
This study is registered on ClinicalTrials.gov as NCT04365660. 
2.3.1. Clinicaltrials.gov Outcomes 
2.3.1.1  Primary Outcome (Outcome 1) 
Title:  Detection of tumor necrosis post-chemotherapy  
Description:  Participants will be assessed with 18F-FTC-146 PET/CT 
imaging at baseline and after neoadjuvant (pre-surgery) chemotherapy but 
before surgery itself.  Chemotherapy will be nominally three 3-week cycles 
administered over up to 12 weeks.  The ability of 18F-FTC-146 PET/CT to 
evaluate treatment effect will be assessed as the percentage of tumor that is 
assessed as necrotic after the treatment course.  The outcome will be 
reported as the mean percentage of the resected tumor (removed by 
surgery) that is assessed by histopathology as necrotic, with standard 
deviation. 
Timeframe:  12 weeks 


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2.3.1.2  Secondary Outcomes 
Outcome 2 
Title:  Maximum Standardized Uptake Value (SUVmax) 
Description:  Participants will be assessed with 18F-FTC-146 PET/CT 
imaging at baseline and after neoadjuvant (pre-surgery) chemotherapy but 
before surgery itself.  Chemotherapy will be nominally three 3-week cycles 
administered over up to 12 weeks.  Based on the PET/CT scans, the 
maximum standardized uptake value (SUVmax) in the tumor region of 
interest (ROI) will be calculated at baseline and after treatment.  The 
outcome will be reported as the mean percent change in SUVmax from 
baseline to post-treatment, with standard deviation.  
Timeframe:  12 weeks 
Outcome 3 
Title:  Use of PROMIS (Patient-Reported Outcomes Measurement 
Information System) to Assess Treatment Effect 
Description:  Participants will receive neoadjuvant (pre-surgery) 
chemotherapy, nominally three 3-week cycles administered over up to 12 
weeks.  The treatment effect of the neoadjuvant chemotherapy will be 
assessed as the change in scores on the PROMIS (Patient-Reported 
Outcomes Measurement Information System) questionnaire, from baseline 
to post-treatment.  The result will be reported as the mean difference from 
baseline to post-treatment, with standard deviation. 
Timeframe:  12 weeks 
2.4. Rationale 
Currently, there is no accurate imaging modality evaluating the amount of necrosis in the 
tumor after neoadjuvant chemotherapy.  This study will evaluate the amount of tracer uptake 
in osteosarcoma tumors prior to chemotherapy and after neoadjuvant chemotherapy.  We 
would also like to see if the uptake correlates with pain.  This is a feasibility study, but we will 
try to correlate the amount of tracer uptake with the amount of necrosis in this small patient 
population.  If there is correlation, we will proceed with a larger study to confirm the results.   
2.5. Preliminary results 
The pre-clinical information below is from a personal communication with 
Brian K Flesner, DVM, MS, DACVIM (Oncology);  Assistant Professor of Oncology, College 
of Veterinary Medicine at the University of Missouri.  
Current evidence for pain/gait outcomes in canine osteosarcoma is described by relatively 
few studies.  Subjective owner questionnaires, force plate analysis, and serum biomarkers 


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have been utilized to assess response.  His group hypothesized that intervention would 
cause objective evidence of pain control when evaluating S1R activity in canine tumors.  
Evaluations of 3 dogs with primary bone cancer included 18F-FTC-146 PET/CT scans, gait 
and kinematic motion analysis, validated owner questionnaires (CBPI), and serum 
N-telopeptide (NTx) concentration.  Dogs received baseline staging;  18F-FTC-146 PET prior 
to treatment and on Day 28;  and Day 0;  7;  14;  and 28 CBPI;  serum banking for NTx;  
orthopedic exam;  and gait analysis.  Each dog received a different treatment:  Dog 1 
received radiation and zoledronate;  Dog 2 received single agent zoledronate;  and Dog 3 
had an amputation.  Dog 1 had a 50% decrease in S1R activity on its day 28 PET scan.  
Dog 2 had a 25% decrease in activity.  Dog 3 will have its second scan in the next few 
weeks.  Both dogs finishing their treatment have had improvement in subjective pain 
assessment.  Data analysis of their CBPI, NTx, and force plate stance are underway. 
2.6. Study Design 
This is an open-label, single-arm phase 2 study to evaluate 18F-FTC-146 PET/CT in 
newly-diagnosed osteosarcoma patients. 
3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
3.1. Inclusion Criteria 
3.1.1 Patients with biopsy-proven osteosarcoma requiring local surgical intervention  
3.1.2 Age ≥ 18 years  
3.1.3 ECOG ≤ 2  
3.1.4 Ability to understand and the willingness to sign a written informed consent document 
3.2. Exclusion Criteria 
3.2.1 Chemotherapy in the past 2 months  
3.2.2 Prior history of allergic reaction to 18F-FTC-146  
3.2.3 Pregnant or nursing  
3.3. 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.   
3.4. Study Timeline 
3.4.1. Primary Completion: 
Primary completion is the date that the final datum is obtained/expected to be obtained 
for the primary outcome.  The timeframe for primary completion for an individual subject 


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CONFIDENTIAL 
is approximately 3 to 4 months from time of consent.  This datum is expected to be 
obtained approximately 12 months from the time the study opens to accrual.   
3.4.2.  Study Completion: 
The study is expected to reach overall completion (last datum from last subject) 
approximately 18 months from the time the study opens to accrual.   
4. IMAGING AGENT/DEVICE/PROCEDURE INFORMATION 
4.1. Treatment / Procedure Plan 
This is a phase 2 study of 18F-FTC-146 PET/CT in patients with newly-diagnosed 
osteosarcoma.  The study will be conducted at Stanford University. 
This study will be conducted over the period in which subjects receive 3 cycles of neoadjuvant 
chemotherapy, which is standard of care.  This time period may vary from subject to subject.  
Each participant will be individually told how long their chemotherapy will take.   
It is anticipated that this study will require approximately 3 days of active participation from each 
study subject and will involve: 
 
Screening assessments,  
 
Two 18F-FTC-146 PET/CT scans 
 
Two PROMIS Questionnaires surveys, ie, Quality of Life (QoL) surveys (Appendix B) 
Participants must sign the IRB-approved consent form prior to participation in any study-specific 
procedure.  
Screening:  Screening assessments must occur within 28 days prior to start of treatment.  
Screening tests, examinations, or procedures include:  
 
Demographics:  Date of birth, sex, ethnicity.  
 
Medical history:  Review of medical history, including surgery and cancer history, other 
cancer treatments subject has received, current and past medicines subject is taking or 
has taken, and reproductive status.  
 
Performance status:  Subject will be asked about their ability to perform everyday tasks.  
 
β-HCG (pregnancy test):  β-HCG must be done within 7 days of first scan.  Subjects who 
are currently pregnant or breast-feeding may not participate in this study.  It is not known 
whether 18F-FTC-146 is safe for the fetus (unborn child) or a breast-fed baby.  
Enrollment: 
Subjects may be enrolled into the study if they meet all eligibility requirements.  
Study Procedures: 
 
2 PET/CT Scans 
 
2 PROMIS QoL surveys  


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The 18F-FTC-146 PET/CT scans and QoL surveys will occur before subjects start chemotherapy 
and the final study visit will occur after subjects have completed chemotherapy.  It is anticipated 
that the entire research study will take approximately 1 year.  
PET/CT:  All subjects in this study will receive 2 PET/CT scans using the experimental 
investigational radiotracer 18F-FTC-146.  After receiving an 18F-FTC-146 PET/CT scan at 
baseline, subjects will receive 3 cycles of neoadjuvant chemotherapy as determined by their 
oncologist.  This treatment is part of subject’s regular medical care.  At the final study visit, after 
completing the 3 cycles of neoadjuvant chemotherapy, subjects will have a 2nd PET-CT scan.  
PROMIS Questionnaires:  At the baseline Study Visit (before first scan) and Final Study Visit 
(before second scan), subjects will be asked to complete questionnaires about pain intensity 
and pain interference with their life.  
Completion of participation: 
Patient’s participation in the study is complete 30 days after the final investigational scan, once the 
PROMIS questionnaire and pathology report have been collected.  
4.2. PET/CT Scan  
 
Radionuclide or imaging agent and chemical form:  18F-FTC-146 
 
Number of radioisotope / imaging agent administrations;  route of administration;  
and administered activity in mCi):  For PET scans, each subject will receive a manual, 
injection of 10 mCi +/- 20% 18F-FTC-146 intravenously; this is usually through a 
peripheral IV line in the extremities, and may also be through a peripherally inserted 
central catheter (PICC line), a Port-A-Cath, or Hickman catheter.  These participants will 
be administered twice with 18F-FTC-146, once at baseline (pre-chemotherapy) and once 
at final study visit (post chemotherapy). 
 
Dosimetry information:  
We estimate that the amount of radiation exposure is about 19.2 mSv, which is 
approximately equal to 38% of the limit that radiation workers (for example, a hospital 
x-ray technician) are allowed to receive in one year. (Hjørnevik, et al, 2017) 
An Exploratory Investigational New Drug (eIND) Application for 18F-FTC-146 
(IND 
) was approved by the Food and Drug Administration (FDA) for 
first-in-human studies to examine radiotracer biodistribution and pharmacokinetics and 
first-in-human studies in typically developing volunteers (N = 10) and patients with pain 
(N = 15) [see reference below] were performed by our group. (Cipriano, et al, 2018;  
Shen B, et al, 2017;  Hjørnevik, et al, 2017) 
Our initial evaluation of 18F-FTC-146 in humans provided evidence that this radiotracer 
is safe and the adsorbed radiation doses measured are acceptable to be used for other 
indications including OCD, HD, and other neurodegenerative diseases. 
(Cipriano, et al, 2018;  Shen B, et al, 2017;  Hjørnevik, et al, 2017)  In May 2018, 
eIND 126459 was successfully converted to the full IND 136678.  


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 
Source of the study agent:  18F-FTC-146 will be prepared under aseptic conditions 
and its quality assessed in the MIPS Cyclotron and Radiochemistry Facility within the 
Division of Nuclear Medicine and Molecular Imaging at Stanford Hospital and Clinics. 
 
Agent ordering:  The agent will be requested by a member of the study team, and prior 
to radiopharmaceutical administration, use of 18F-FTC-146 will be approved and 
prescribed by a study investigator or sub-investigator.  
 
Radionuclide / imaging agent management, control, and security :  A member of 
the research team trained in radiation safety will securely transport the dose of 
18F-FTC-146 to the PET/CT suite in the Stanford Nuclear Medicine for imaging.  The 
nuclear medicine technologist will follow radiation safety procedures when checking in 
the package. 
 
Scan description (for well-established imaging procedures):  A low-dose CT will be 
obtained from vertex to toes; this will use 120 kV and dose modulation based on body 
habitus, ranging 10 to 105 mA.  This will be followed by 30 to 60-minute limited dynamic 
PET emission scan in a region of interest of known osteosarcoma (a 30-minute scan will 
be obtained for most patients; this may be extended for up to 60 minutes in 
1 to 2 patients).  Immediately after the limited dynamic scan, a static whole-body PET 
emission scan will be acquired (approximately 25 minutes). 
 
Number of scans to be performed on a single research subject:  Each subject will 
receive 2 PET/CT scans. 
 
For each imaging procedure provide the setup and technique sufficient to permit 
research subject radiation dose modeling:  The chief technologist can usually provide 
this information.  Set up will be according to standard institutional practice for whole 
body PET/CT scans. 
5. STUDY PROCEDURES   
5.1. 
Criteria for Removal from Study 
Subjects will be removed from the study if there is withdrawal of consent, non-compliance, or 
if the subject is female and has become pregnant. 
5.2 
Alternatives 
The alternative is to not be on this study and receive standard of care treatment. 


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6. STUDY CALENDAR 
 
Screening b 
Baseline 
(Pre-chemo)  
Final Visit e 
Investigational Scan a 
 
X 
X 
Informed consent  
X 
 
 
Demographics  
X 
 
 
Medical history  
X 
 
 
Height  
 
X 
 
Weight  
 
X 
 
Performance status  
X 
 
 
β-HCG  
X 
 
 
PROMIS Questionnaires  
 
X c 
X c 
Adverse event evaluation d 
 
X 
X 
Pathology report 
 
 
X e 
a Patients will receive neoadjuvant chemotherapy, which is standard of care.  It is not part of this 
protocol.  Neoadjuvant chemotherapy will start after baseline investigational scan.  The second 
investigational scan will occur after neoadjuvant chemotherapy.  
b Screening:  Screening period is 28 days.  β-HCG must be done within 7 days of first scan.  
c Patients will complete PROMIS questionnaires at Baseline (before 1st scan) and at Week 9 (before 
2nd scan).  Questionnaire may be completed within 2 weeks prior to each investigational scan.  
d Adverse events:  Adverse events will be recorded from the time of the first investigational scan and for 
30 days from the time of the final investigational scan.  Only AEs related to PET/CT procedure will be 
collected and recorded.  
e Patient’s participation in the study is complete 30 days after the final investigational scan, once the 
PROMIS questionnaire and pathology report have been collected.  
7. ADVERSE EVENTS AND REPORTING PROCEDURES 
7.1. Potential Adverse Events 
The patients will be injected with 18F-FTC-146, which is an investigational drug.  An IND 
application has previously been filed with FDA (IND 
  IND-holder 
Guido Davidzon, MD).  Toxicity studies performed by unbiased party have shown no 
treatment related toxicity at 3 and 15 days after treatment with a single dose (250-fold the 
expected clinical dose) in a single rodent species.  There are no known pharmacological 
risks of the drug.  However, there is risk of radiation dose as described below.   
This research study involves exposure to radiation from two 10 mCi +/- 20% doses of 
18F-FTC-146.  The radiation exposure from two 10 mCi +/- 20% doses of 18F-FTC-146 is 


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CONFIDENTIAL 
maximally 19.2 mSv, which is approximately equal to 38% of the limit that radiation workers 
(for example, a hospital X-ray technician) are allowed to receive in 1 year.  This amount of 
radiation involves minimal risk and is necessary to obtain the research information desired.   
7.2. Adverse Event Reporting 
Adverse events will be graded according to CTCAE v5.0.  Both Serious and Non-Serious 
Adverse Events will be clearly noted in source documentation and listed on study-specific 
Case Report Forms (CRFs).  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.  
Only adverse events related to PET/CT procedure will be captured.  All Serious Adverse 
Events (SAEs) will be tracked until resolution and 30 days after the last investigational scan.   
8. REGULATORY CONSIDERATIONS 
8.1. Institutional Review of Protocol 
The protocol, the proposed informed consent and all forms of participant information related 
to the study (eg, advertisements used to recruit participants, questionnaires) 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. 
8.2. Data Management Plan 
The research coordinator will be responsible for database records of subject data.  The data 
will be kept in an OnCore online database, under password protection with access limited to 
specific areas of the database.  A chart with all of the relevant research subject information 
will be maintained for each subject by the research coordinator.  Subject charts will be 
reviewed by Stanford PI and Study Coordinator for yearly audits.   
8.3. Data and Safety Monitoring Plan 
The Protocol Director will oversee the conduct of the trial.  
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 
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, medical notes, 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. 


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9. MEASUREMENTS   
9.1. Primary and Secondary Endpoints 
1.  Histologically-determined percentage of necrosis in post-chemotherapy resected 
tumor. 
2.  Pre- and post-treatment SUVmax in tumor ROI, and the pre-post percent change. 
3.  Pre- and post-treatment pain score, and the pre-post difference. 
9.2. Measurement Methods 
1. Assessment of necrosis in osteosarcoma specimens is performed by subspecialized 
bone-soft tissue pathologists and pediatric pathologists.  The resection specimen is 
sequentially sliced at 0.5 cm intervals to yield a series of macrosections.  A full single 
macrosection, including tumor, is entirely submitted for microscopic evaluation with 
the coordinates of histologic sections mapped to a photograph of the macrosection.  
Histologic assessment of the proportion of viable tumor is performed on H&E-stained 
sections. 
2. PET SUVmax will be measured in an ROI drawn over the lesion (based on CT). 
3. Patients will rate pain level using PROMIS (Patient-Reported Outcome Measurement 
Information System) Questionnaires. 
9.3. Measurement Time Points 
1.  Imaging and pain measurements will be made just before and after treatment 
(3 cycles of chemotherapy). 
2.  Tumor histology will be measured on the post-chemotherapy resected tumor, after 
the second PET/CT scan.  
10. STATISTICAL CONSIDERATIONS 
10.1. Statistical Design 
This is an one-arm, non-randomized prospective cohort study. 
10.2. Descriptive Statistics and Exploratory Data Analysis 
Descriptive statistics and correlations will be calculatedconsisting of the means, medians, 
and standard deviations of: 
1. Histologically determined percentage of necrosis in post-chemotherapy resected 
tumor. 
2. Pre- and post-treatment SUVmax in tumor region of interest (ROI), and the pre-post 
percent change. 
3. Pre- and post-treatment pain score, and the pre-post difference. 


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10.3. Primary Analysis  
10.3.1. Analysis Population 
All enrolled subjects. 
10.3.2. Analysis Plan 
1.  The following will be recorded for each patient 
(a) the histological percentage of necrosis and 
(b) the percent reduction in SUVmax. 
2.  The histological percent necrosis will be plotted against SUVmax percent reduction to 
calculate rank correlation. 
10.4. Secondary Analysis 
10.4.1. Analysis Population 
All enrolled subjects. 
10.4.2. Analysis Plan 
1.  The following will be recorded for each patient 
(a) the post-treatment reduction in pain score.  
(b) the percent reduction in SUVmax.  
2.  The reduction in pain score will be plotted against SUVmax reduction to calculate 
rank correlation.  
10.5. Sample Size 
Preliminary approval for this study is for 5 subjects only.  An eventual sample size of 20 will 
provide 90% power at one-sided 5% error to detect a correlation as low as 0.60.  
10.6. Accrual estimates 
Stanford treats roughly 8 to 10 adult osteosarcoma patients per year.  We expect to be able 
to recruit at least half of them.  
10.7. Criteria for future studies 
This study will be judged to be successful if both:  
(a) the correlation between necrosis and PET signal reduction is ≥ 0.60.  
(b) the correlation between pain reduction and PET signal reduction is ≥ 0.60.  


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11. REFERENCES 
Cipriano PW, Lee SW, Yoon D, et al.  “Successful treatment of chronic knee pain following 
localization by a sigma-1 receptor radioligand and PET/MRI:  a case report.”  Journal of Pain 
Research.  2018;11:2353.   
Shen B, Park JH, Hjørnevik T, et al.  “Radiosynthesis and First-In-Human PET/MRI 
Evaluation with Clinical-Grade 18F-FTC-146.”  Molecular Imaging and Biology.  
2017;19(5):779-786.   
Hjørnevik T, Cipriano PW, Shen B, et al, Gambhir SS.  “Biodistribution and radiation 
dosimetry of 18F-FTC-146 in humans.”  Journal of Nuclear Medicine.  
2017;58(12):2004-2009. 


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Appendix A:  Inclusion/Exclusion Criteria Checklist 
*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.   
Protocol Information  
Protocol Title: A Phase 2 Study of 18F-FTC-146 PET/CT in Patients with 
Newly-Diagnosed Osteosarcoma 
eProtocol number: 
OnCore number: 
IRB-52746  
SARCOMA0041  
Principal Investigator: Kristen Ganjoo, MD 
 
Subject Unique ID:  SAR41-____ ____ 
Inclusion Criteria 
(From IRB-approved protocol) 
Yes 
No 
Supporting 
Documentation* 
1. Patients with biopsy-proven osteosarcoma 
requiring local surgical intervention.   
 
 
      
2. Age ≥ 18 years  
 
 
      
3. ECOG ≤ 2 
 
 
      
4. Ability to understand and the willingness to 
sign a written informed consent document. 
 
 
      
Exclusion Criteria 
(From IRB-approved protocol) 
 
1. Chemotherapy in the past 2 months. 
 
 
      
2. Prior history of reaction to 18F-FTC-146. 
 
 
      
3. Pregnancy or nursing patients 
 
 
      


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IV.  Statement of Eligibility 
This subject is [ 
 eligible / 
 ineligible ] for participation in the study. 
Study Coordinator printed name: 
Date:  
Signature: 
 
Investigator printed name: 
Date:  
Signature: 
 
Triple-check reviewer printed name: 
Date:  
Signature: 
 


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CONFIDENTIAL 
Appendix B:  PROMIS (Patient-Reported Outcomes Measurement Information System) 
Questionnaires 


PROMIS Item Bank v.1.0 – Pain Intensity – Scale
Pain Intensity – Scale
Please respond to each item by marking one box per row.
In the past 7 days…
Had no 
pain
Mild
Moderate
Severe
Very 
severe
PAINQU6 
How intense was your pain at its worst?....
1
2
3
4
5
PAINQU8 
How intense was your average pain?.........
1
2
3
4
5
No pain
Mild
Moderate
Severe
Very 
severe
PAINQU21 
What is your level of pain right now?........
1
2
3
4
5
6 March 2017
© 2008-2017 PROMIS Health Organization and PROMIS Cooperative Group
Page 1 of 1


 
PROMIS SF v.1.0  Pain Intensity 3a 
 
Spanish (Universal) 
06 September 2012 
 
© 2008-2012 PROMIS Health Organization and PROMIS Cooperative Group 
Page 1 of 1 
Intensidad del dolor  Cuestionario abreviado 3a 
 
 
Responda a cada pregunta marcando una casilla por línea. 
 
En los últimos 7 días 
 
No tuve 
dolor 
Muy poco 
Moderado 
Intenso 
Muy 
intenso 
 
 
 
 
 
 
PAINQU6 
¿Qué intensidad tuvo el dolor en su peor 
momento? ...................................................
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 
 
 
 
PAINQU8 
¿Qué intensidad tuvo el dolor que sintió 
en su punto medio? ....................................
 
1 
 
2 
 
3 
 
4 
 
5 
 
Ningún 
dolor 
Muy poco 
Moderado 
Intenso 
Muy 
intenso 
PAINQU21
¿Cuál es su nivel de dolor en este 
momento? ...................................................
 
1 
 
2 
 
3 
 
4 
 
5 


PROMIS Item Bank v1.0 – Pain Interference – Short Form 4a
Pain Interference – Short Form 4a
Please respond to each question or statement by marking one box per row.
In the past 7 days…
Not at all
A little bit
Somewhat
Quite a bit
Very much
PAININ9 
How much did pain interfere with your 
day to day activities?.................................
1
2
3
4
5
PAININ22 
How much did pain interfere with work 
around the home?......................................
1
2
3
4
5
PAININ31 
How much did pain interfere with your 
ability to participate in social 
activities? ...............................................
1
2
3
4
5
PAININ34 
How much did pain interfere with your 
household chores?...................................
1
2
3
4
5
2 June 2016
© 2008-2016 PROMIS Health Organization and PROMIS Cooperative Group         Page 1 of 1


PROMIS Item Bank v1.0  Pain Interference  Short Form 4a 
Spanish (Universal) 
06 September 2012 
 
Investigator Format    © 2008-2012  PROMIS Health Organization and PROMIS Cooperative Group           Page 1 of 1 
 
Efectos del dolor  Cuestionario abreviado 4a 
Responda a cada pregunta o enunciado marcando una casilla por línea. 
 
En los últimos 7 días ... 
Nada 
Un poco 
Algo 
Mucho 
Muchísimo 
PAININ9
1
¿En qué medida el dolor interfirió en sus 
actividades diarias?  .................................. 
 
1 
 
2 
 
3 
 
4 
 
5 
PAININ22 
2
¿En qué medida el dolor interfirió en el 
trabajo en el hogar?  ...................................
 
1 
 
2 
 
3 
 
4 
 
5 
PAININ31 
3
¿En qué medida el dolor interfirió en su 
capacidad para participar en actividades 
sociales?..................................................... 
 
1 
 
2 
 
3 
 
4 
 
5 
PAININ34 
4
¿En qué medida el dolor interfirió en sus 
tareas domésticas? ..................................  
 
1 
 
2 
 
3 
 
4 
 
5