Conditions: Non-small Cell Lung Cancer Starting Pemetrexed Based Therapy Unresectable Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 3
Healthy volunteers: no

Brief summary:
The investigators will test the hypothesis that positron emission tomography (PET) imaging with the imaging agent 18F-thymidine (FLT) can rapidly assess treatment response in patients with unresectable non-small cell lung cancer (NSCLC).

Detailed description:
We will test the hypothesis that positron emission tomography (PET) imaging with the imaging agent 18F-thymidine (FLT) can rapidly assess treatment response in patients with non-small cell lung cancer (NSCLC). In particular, we hypothesize that FLT-PET imaging will offer the potential of rapidly triaging therapy efficacy within hours to days following the start of therapy start by non-invasively monitoring metabolic changes in the tumor, rather than the conventional approach of waiting months for tumors to grow or shrink on computed tomography (CT).

We propose two approaches to evaluate the potential of FLT-PET for assessment of response to therapy in NSCLC. In the first, we will exploit a specific effect (the FLT "flare") induced by pemetrexed, which is first-line chemotherapy for non-squamous NSCLC, to evaluate the utility of FLT-PET to assess successful response to pemetrexed (PEM) therapy within 24 hours. In the second approach, we will utilize FLT as a marker of cell proliferation, as has been done in other cancers, to determine whether chemotherapy has produced a decrease in tumor growth at 2 weeks after starting therapy. Since approximately 70% of patients will fail PEM-based therapy, an imaging technique that could reliably detect PEM efficacy in hours to days rather than months would save valuable time and allow for switch to a more effective therapy.

Arms:
arm 1: All patients enrolled in the study will receive three 18F-thymidine (FLT) PET/CT scans at the following timepoints: before therapy, on the day of starting pemetrexed therapy (within 24 hours of starting pemetrexed) and at 2-4 weeks of starting pemetrexed therapy.

Interventions: intervention 1: Baseline 18F-thymidine (FLT) PET/CT intervention 2: Post-therapy 18F-thymidine (FLT) PET/CT to assess for pemetrexed induced tumor FLT "flare" intervention 3: Post-therapy 18F-thymidine (FLT) PET/CT to assess for pemetrexed induced changes in tumor proliferation
Intervention descriptions: intervention 1: FLT is a fluoro-labelled thymidine analog used as a radiotracer of tumor proliferation in PET/CT imaging. This baseline scan will be used to compare post-therapy FLT-PET/CT in order to assess change in tumor accumulation of FLT. intervention 2: FLT is a fluoro-labelled thymidine analog used as a radiotracer of tumor proliferation in PET/CT imaging. This scan will be performed on the day of starting pemetrexed therapy (within 24hrs of starting pemetrexed) and used to compare to baseline FLT-PET/CT in order to assess change in tumor accumulation of FLT. The objective is to assess for early pemetrexed induced changes in tumor accumulation of FLT known as FLT "flare". intervention 3: FLT is a fluoro-labelled thymidine analog used as a radiotracer of tumor proliferation in PET/CT imaging. This scan will be performed 2-4 weeks after starting pemetrexed therapy and used to compare to baseline FLT-PET/CT in order to assess change in tumor accumulation of FLT. The objective is to assess for pemetrexed induced changes in tumor accumulation of FLT as a surrogate measure of tumor proliferation.

Protocol document:
Prot_SAP_000.pdf: 
  
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study 
sponsor 
 
 
 
 
 
 
 
 
Serial [18F]Fluorothymidine (FLT)PET/CT as a Biomarker of Therapeutic Response 
in Pemetrexed Therapy for Non-Small Cell Lung Cancer 
 
 
Principal Investigator: 
Sharyn I Katz, MD, MTR 
Department of Radiology 
Hospital of the University of Pennsylvania 
One Silverstein Building 
3400 Spruce Street 
Philadelphia, PA 19104 
Sponsor: 
 
 
 
Funding Sponsor: 
The Department of Radiology, University of Pennsylvania, 
School of Medicine 
 
 
Department of Radiology 
Hospital of the University of Pennsylvania 
One Silverstein Building 
3400 Spruce Street 
Philadelphia, PA 19104 
 
Study Product: 
 
[18F]-fluorothymidine (FLT) 
 
Protocol Number: 
 
820328 (UPCC 15514) 
 
IND Number: 
 
NCT Number: 
 
102,482 
 
02274038 
 
 
 
 
 
 
 
 
 
 
 
Current Protocol Version Date: 4/1/2016 
Previous Protocol Version Date: 6/23/2015 
 
 
CLINICAL RESEARCH PROTOCOL 


Serial [18F]Fluorothymidine (FLT)PET/CT as a Biomarker of Therapeutic Response in Pemetrexed 
Therapy for Non-Small Cell Lung Cancer 
 
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sponsor 
Table of Contents 
 
STUDY SUMMARY ..................................................................................................................................... 1 
SCHEMA ..................................................................................................................................................... 2 
INTRODUCTION ......................................................................................................................................... 3 
1 
BACKGROUND .................................................................................................................................. 3 
1.1 
INVESTIGATIONAL AGENT .............................................................................................................. 3 
1.2 
RATIONALE ................................................................................................................................... 3 
1.3 
DOSE RATIONALE AND RISK/BENEFITS ASSESSMENT ...................................................................... 8 
2 
STUDY OBJECTIVES ........................................................................................................................ 9 
3 
STUDY DESIGN ................................................................................................................................. 9 
3.1 
GENERAL DESIGN ......................................................................................................................... 9 
3.2 
PRIMARY STUDY ENDPOINTS ....................................................................................................... 10 
3.3 
SECONDARY STUDY ENDPOINTS .................................................................................................. 10 
4 
SUBJECT SELECTION AND WITHDRAWAL ................................................................................. 11 
4.1 
INCLUSION CRITERIA ................................................................................................................... 11 
4.2 
EXCLUSION CRITERIA .................................................................................................................. 11 
4.3 
SUBJECT RECRUITMENT AND SCREENING .................................................................................... 11 
4.4 
SUBJECT WITHDRAWAL ............................................................................................................... 11 
5 
INVESTIGATIONAL AGENT ............................................................................................................ 12 
5.1 
DESCRIPTION ............................................................................................................................. 12 
5.2 
PREPARATION OF STUDY DRUG ................................................................................................... 12 
5.3 
STUDY DRUG RECEIPT AND ADMINISTRATION: [18F]FLT ................................................................ 13 
6 
STUDY PROCEDURES .................................................................................................................... 13 
6.1 
INITIAL PRE-STUDY SCREENING PRIOR TO [18F]FLT PET/CT SCAN ................................................. 13 
6.2 
[18F]FLT PET/CT IMAGING VISIT ................................................................................................. 14 
6.3 
[18F]FLT PET/CT IMAGE ANALYSIS ............................................................................................. 14 
6.4 
POST-FLT-PET/CT FOLLOW-UP ................................................................................................. 14 
7 
STATISTICAL PLAN ........................................................................................................................ 15 
7.1 
SAMPLE SIZE DETERMINATION ..................................................................................................... 15 
7.2 
STATISTICAL METHODS ............................................................................................................... 15 
8 
SAFETY AND ADVERSE EVENTS ................................................................................................. 15 
8.1 
DEFINITIONS ............................................................................................................................... 15 
8.2 
RECORDING OF ADVERSE EVENTS ............................................................................................... 17 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ................................ 17 
8.3.1 
Investigator reporting: notifying the study sponsor ............................................................... 17 
8.3.2 
Investigator reporting: notifying the Penn IRB ...................................................................... 18 
8.3.3 
Sponsor reporting: Notifying the FDA .................................................................................. 18 
8.3.4 
Sponsor reporting: Notifying participating investigators ....................................................... 19 
8.4 
MEDICAL MONITORING ................................................................................................................ 19 
9 
DATA HANDLING AND RECORD KEEPING .................................................................................. 19 
9.1 
CONFIDENTIALITY ........................................................................................................................ 19 
9.2 
SOURCE DOCUMENTS ................................................................................................................. 19 
9.3 
CASE REPORT FORMS ................................................................................................................ 20 
9.4 
RECORDS RETENTION ................................................................................................................. 20 


Serial [18F]Fluorothymidine (FLT)PET/CT as a Biomarker of Therapeutic Response in Pemetrexed 
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10 
STUDY MONITORING, AUDITING, AND INSPECTING ................................................................. 20 
10.1 
STUDY MONITORING PLAN .......................................................................................................... 20 
FREQUENCY ............................................................................................................................................ 20 
10.2 
REGULATORY DOCUMENTS REVIEWED ......................................................................................... 21 
10.3 
DOCUMENTATION OF THE MONITORING VISIT ................................................................................ 21 
10.4 
AUDITING AND INSPECTING .......................................................................................................... 21 
11 
ETHICAL CONSIDERATIONS ......................................................................................................... 21 
12 
STUDY FINANCES ........................................................................................................................... 22 
12.1 
FUNDING SOURCE ...................................................................................................................... 22 
12.2 
CONFLICT OF INTEREST ............................................................................................................... 22 
12.3 
SUBJECT STIPENDS OR PAYMENTS .............................................................................................. 22 
13 
REFERENCES .................................................................................................................................. 22 
 
  
APPENDIX…………………………………………………………………………………………………….... 
 
 


Serial [18F]Fluorothymidine (FLT)PET/CT as a Biomarker of Therapeutic Response in Pemetrexed 
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List of Abbreviations 
 
 
 
FLT  
3'-deoxy-3'-[18F]-fluorothymidine (FLT) 
 
PET 
positron emission tomography 
 
CT 
computed tomography 


FLT-PET/CT as a Biomarker of Therapeutic Response in Pemetrexed Therapy for Non-Small Cell Lung 
Cancer 
 
 
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sponsor 
Study Summary 
Title 
Serial [18F]Fluorothymidine (FLT)PET/CT as a Biomarker of Therapeutic 
Response in Pemetrexed Therapy for Non-Small Cell Lung Cancer 
Short Title 
Serial [18F]FLT PET/CT in NSCLC 
Protocol Number 
 
Study Design 
Proof of concept study of serial [18F]fluorothymidine (FLT) as an imaging tracer 
for positron emisssion tomography (PET/CT) for imaging non-small cell lung 
cancer receiving pemetrexed therapy. 
Study Duration 
5-7 years 
Study Center(s) 
University of Pennsylvania 
Objectives 
Evaluation of [18F]fluorothymidine (FLT) as an imaging tracer for PET/CT 
imaging of non-small cell lung cancer(NSCLC). Compare pre- and post-
treatment primary tumor uptake for FLT-PET/CT and correlate with clinical 
markers of response. PET/CT tumor metabolic response will also be correlated 
will to progression-free survival and overall survival. When tumor biopsy 
specimens are available, correlation will be made with the FLT-PET/CT 
metabolic response and histological markers including Ki67 staining, a 
measure of % nuclei actively engaged in cellular division. 
Number of Subjects 
Target accrual is 20 evaluable subjects; up to 30 subjects may be enrolled to 
reach this target goal 
Diagnosis and Main 
Inclusion Criteria 
Adult men and women of any ethnicity with NSCLC deemed unresectable by 
CT or PET imaging criteria and planning to start pemetrexed-based therapy. 
Study Product 
[18F]-fluorothymidine ([18F]FLT)  
Statistical 
Methodology 
Due to the exploratory nature of this pilot study of 30 patients, no tests of 
hypothesis are planned. Descriptive statistics for all variables of interest will be 
tabulated and graphically displayed by various classifications, in order to 
assess feasibility, justify sample size and aid in the planning of a more rigorous 
proposed subsequent hypothesis driven trial. 
 
 
 
 
 
 
 


Serial [18F]Fluorothymidine (FLT)PET/CT as a Biomarker of Therapeutic Response in Pemetrexed 
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STUDY DESIGN 
 
Serial [18F]Fluorothymidine (FLT)PET/CT imaging as a measure of therapeutic response 
in patients with newly diagnosed small cell lung cancer  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
Diagnosis of non-small cell lung cancer 
• 
Eligible and willing to consent for imaging protocol 
• 
Planning to start systemic therapy  
[18F]FLT PET/CT scan  
Systemic therapy started 
Baseline 
 Day of therapy start 
(when possible; either 
1st or 2nd cycle)  
[18F]FLT PET/CT scan  
Consent and Enrollment 
[18F]FLT PET/CT scan  
At least 2 weeks 
following the start of 
the chosen cycle of  
therapy. 
Evaluation of clinical response  
Long term follow up:             
Progression-free survival and 
overall survival recorded 


Serial [18F]Fluorothymidine (FLT)PET/CT as a Biomarker of Therapeutic Response in Pemetrexed 
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Introduction 
This document is a protocol for a human research study. This study is to be conducted 
according to US and international standards of Good Clinical Practice (FDA Title 21 part 312 
and International Conference on Harmonization guidelines), applicable government regulations 
and Institutional research policies and procedures.  
1 Background 
1.1 Investigational Agent 
3'-deoxy-3'-18F fluorothymidine ([18F]FLT) is a structural analog of the DNA 
nucleoside, thymidine (Figure 1).  [18F]FLT is a radiolabeled imaging agent that has been 
proposed for investigating cellular proliferation in normal bone marrow and changes with 
targeted radiotherapy with positron emission tomography (PET).  Although [18F]FLT is 
not incorporated into DNA, it is phosphorylated by thymidine kinase, an intracellular 
enzyme of the proliferation pathway that is upregulated in proportion to DNA synthesis.  
The phosphorylated, [18F]FLT is trapped in the cell.  Thus, FLT has potential as a marker 
of proliferating cells in proportion to the DNA synthesis rate.  Therefore, [18F]FLT is 
proposed as a radiolabeled PET imaging probe for in vivo assessment of cellular 
proliferation in malignant tumors. For complete information, please refer to the 
Investigator’s Brochure for [18F]FLT. 
 
 
 
 
Figure 1.The chemical structures of FLT and thymidine 
 
1.2 Rationale 
BACKGROUND:  
A need for early response assessment in NSCLC 
Unresectable, locally advanced non-small cell lung cancer 
(NSCLC) has an extremely poor prognosis with a median 
survival time of 9 to 11 months1. Pemetrexed (PEM) along with 
a platinum-based antineoplastic (cisplatin or carboplatin), a 1st-
line therapy for non-squamous NSCLC, has a response rate of 
20-30%, meaning that that 70-80% of patients fail to respond to 
PEM-based therapy2, 3.  Currently, assessment of response to 
therapy relies on CT changes in tumor size (CT Response 
Evaluation Criteria In Solid Tumors; RECIST 1.1)4; however, 
these measurements are conducted typically after 3 x 3-week 
cycles (9 weeks) of chemotherapy, often with associated 
delays, and thus patients with unresectable locally advanced 


Serial [18F]Fluorothymidine (FLT)PET/CT as a Biomarker of Therapeutic Response in Pemetrexed 
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NSCLC now spend up to one-third of their expected life-span waiting just to see if their therapy is 
working.  Moreover, the need for earlier response assessment is critical for clinical trials in 
NSCLC, where delays in response assessment lead to increased costs, unwarranted toxicities, 
and potential loss of lives.   
 
[18F]FLT “flare” effect; exploiting a drug-drug interaction: DNA replication, whether in normal 
or cancer cells, requires thymidine5, a fact exploited by a number of chemotherapeutic agents6 
including PEM2, 3. Two parallel pathways, the de novo and DNA salvage pathways (Fig. 1), source 
thymidine for the dividing cell.  Pharmacologic inhibition of thymidylate synthase (TS) by PEM2 
inhibits de novo pathway activity, resulting in a transient (< 24 hours of start of therapy7, 8) burst 
of metabolism through the salvage pathway, an 
effect measurable with 18F-thymidine ([18F]FLT) 
as a tracer of the salvage pathway7-13; when 
salvage pathway activity increases, cells 
become increasingly more [18F]FLT avid. Since 
TS over expression/over activity results in PEM 
resistance of NSCLC14-17 we hypothesize that 
[18F]FLT “flare,” which represents a burst in 
tumor [18F]FLT avidity induced by TS-inhibition, will predict successful PEM-based therapy in 
NSCLC and will permit determination of effective PEM-based therapy within 1 day of initiation. It 
is also apparent through the published clinical trials12, 13, 18 on [18F]FLT “flare”, that choice of time 
point to measure [18F]FLT “flare” may affect association with tumor metabolism. Since data 
suggests that imaging as soon as possible following starting TS inhibition, we will conduct [18F]FLT 
PET/CT for measurement of “flare”  as immediately as possible following completion of 
pemetrexed infusion (on same day of pemetrexed infusion), at the start of either the 1st or 2nd 
cycle of therapy. 
 
[18F]FLT as a measure of proliferation: [18F]FLT is a reliable biomarker of proliferation19 and 
using [18F]FLT as a marker of tumor proliferative activity has been the most successful 
application of [18F]FLT to date.  As a chemotherapeutic begins to successfully impact the tumor 
metabolism, tumor proliferation generally falls below baseline. This post-therapeutic change in 
tumor avidity for [18F]FLT has been demonstrated to predict therapeutic response within a few 
weeks from the start of therapy in a range of malignancies20-24, including NSCLC25. However, 
[18F]FLT PET/CT therapy response as a function of successful TS-inhibition, a commonly used 
therapeutic strategy, has not been well studied in NSCLC.  By 2 weeks of therapy, any transient 
“flare” phenomenon will have dissipated and tumor avidity for [18F]FLT should reflect overall 
tumor proliferation rate, which is expected 
to decrease with successful therapy. We 
hypothesize that a fall in NSCLC tumor 
avidity for [18F]FLT after 2 weeks of PEM-
based therapy will be predictive of 
therapy success and the stable to 
increased FLT avidity at 2 weeks will 
predict therapy failure. It is important to 
note that the [18F]FLT “flare” response, a 
direct pharmacological effect, and the 
delayed decrease in [18F]FLT avidity, a 
measured therapy effect on tumor 
metabolism, occur by different 
mechanisms (Table 1) providing 
complementary strategies for assessing 


Serial [18F]Fluorothymidine (FLT)PET/CT as a Biomarker of Therapeutic Response in Pemetrexed 
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tumor response.  While the “flare” response is specific for TS inhibition (i.e. PEM), post-therapy 
decreased tumor avidity for [18F]FLT should occur with any successful chemotherapy. 
 
HYPOTHESES/OBJECTIVES: Our overarching hypothesis is that [18F]FLT PET/CT will allow early 
assessment of therapeutic response in NSCLC.  Our primary objective (Table 1) is to assess 
whether [18F]FLT “flare”, a transient drug-induced burst of DNA salvage pathway activity, is 
predictive of PEM-based therapy success. Our secondary objective is to determine whether 
[18F]FLT PET/CT measured post-therapy changes in tumor proliferation correlate with PEM-
based therapy clinical outcome.  
 
Specific Aim 1: To conduct a proof-of-concept clinical study of tumor [18F]FLT “flare” and 
[18F]FLT -measured changes in tumor proliferation as predictors of NSCLC response to PEM-
based therapy (Fig 2). Hypothesis: NSCLC [18F]FLT “flare” in the 1 day of a cycle of therapy and 
FLT proliferative response at least 2 wks later will predict clinical response to PEM-based 
therapy. 
1.3 Dose Rationale and Risk/Benefits Assessment 
[18F]fluorothymidine ([18F]FLT) is an investigational imaging drug, which has been 
extensively used in oncologic PET imaging with no evidence of pharmacological effect. No 
adverse events have been reported in a large number of published studies of human 
experience for [18F]FLT at the strength to be used for this study, doses ranging from 3-15 
mCi have been reported in the literature with a large number of studies showing that a 
dose of approximately 5 mCi is safe and produces high quality images.  The [18F]FLT 
dose anticipated for this study will be 5.0 mCi ± 20%. Assuming a 70kg individual, the 
maximum concentration of [18F]FLT would be expected to be equivalent to 0.29 ng-h/mL.  
 
Risk/Benefit 
The patients will undergo 3 study FLT-PET/CT examinations for the purposes of this 
study. [18F]FLT is a positron emitting radiopharmaceutical. As such, it poses and intrinsic 
radiation exposure risk. However, when administered in low tracer doses as a PET 
imaging agent, as described in this protocol, this risk is felt to be extremely small. The 
organ and total body doses associated with FLT PET imaging are felt to be comparable to 
those associated with other widely used clinical nuclear medicine procedures.  
 
To date approximately 2416 humans have been studied with [18F]FLT in published 
literature. There have been no reported AEs associated with the used of [18F]FLT and no 
adverse reactions are expected as a result of the IV injection of [18F]FLT. We will continue 
to monitor this information ass the study progresses, including reviewing current literature 
and our in-house medical monitoring of this study.  
 
There is potential with intravenous injections, including [18F]FLT, for allergic reactions. 
This has not been observed in the published human exposure to date. The dose will be 
delivered intravenously by skilled clinical professionals and patients will be monitored for 
any signs or symptoms of allergic reaction by trained personnel for the duration of the 
PET procedure. The injection site may show bruising, bleeding, inflammation or infection.  
  
No psychological, social or legal risk is expected. While loss of confidentiality is possible, 
it is felt to be very unlikely due to the small number of professionals involved in the study 
with knowledge of this information. All clinicians and research staff involved are well 
trained in HIPAA practices. 
 


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The risk to the patient is felt to be minimal with only the added radiation considered the 
likely risk posed to the patient and this radiation is considered acceptable. It is not unusual 
for oncologic patients to receive multiple radiological tests, including multiple PET/CT 
scans, in the course of clinical management. This study proposes the addition of 3 
PET/CT scans to the patients care. There is potential benefit to the patient and to general 
society if FLT-PET/CT proves to be a useful imaging agent for the detection of response 
to cancer therapy.  Pilot data from this study will be used to adequately power larger 
studies evaluating FLT-PET/CT as a measure of tumor response to therapy. 
2 Study Objectives 
 
Primary Objectives:  
• 
Evaluation of [18F]fluorothymidine ([18F]FLT) as an imaging tracer for PET/CT 
imaging of small cell lung cancer.  
• 
Compare pre- and post-treatment primary tumor uptake for FLT-PET/CT and 
correlate with clinical markers of response.  
Secondary Objectives: 
• 
PET/CT tumor metabolic response will be correlated will to time-to-progression and 
survival.  
• 
Correlate FLT-PET/CT uptake measures and histological markers, including Ki-67 
staining, a measure of % nuclei actively engaged in cellular division when biopsy 
tissue is available.  
 
3 Study Design 
 
3.1 Study Design: This is a pilot study in patients with a diagnosis of non-small cell lung 
cancer with at least one lesion that is ≥ 1 cm on at least one type of standard imaging (e.g. 
CT, chest x-ray, MRI). Patients may participate in this study if they are greater than 18 
years of age, most participants will be receiving care at the clinical practices of the 
University of Pennsylvania. Patients that meet the eligibility criteria will be approached 
about study participation regardless of race or ethnic background. We anticipate enrolling 
up to 30 participants with diagnosed non-small cell lung cancer beginning a new line of 
therapy who meet eligibility requirements for this study. The target accrual goal is to reach 
20 evaluable patients who complete 2 or 3 FLT PET/CT scans, in order to reach this target 
we may enroll up to 30 subjects. Thus, accrual is estimated to occur over approximately 5 
years. 
 
Positron emission tomography (PET) imaging will be used to evaluate cell proliferation in 
sites of non-small cell lung cancer using the investigational radiotracer [18F]FLT.  Study 
imaging will be performed using a whole-body PET/CT scanner (Philips Medical Systems, 
Netherland). The protocol will be performed under the regulatory approval of the 
(Institutional Review Board) IRB and FDA IND.  
 
A baseline FLT-PET/CT will be obtained no more than 1 week prior to initiation of the 
chosen cycle therapy to assess baseline, pre-therapy tumor proliferative activity. On the 
day of 1st infusion of pemetrexed therapy of either cycle 1 or 2 of therapy, a post-therapy 
FLT-PET/CT will be obtained, when possible. There may be patients that will be unable to 
obtain this 2nd FLT-PET/CT scan due to scheduling/feasibility issues and those patients will 


Serial [18F]Fluorothymidine (FLT)PET/CT as a Biomarker of Therapeutic Response in Pemetrexed 
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forgo the 2nd FLT-PET/CT (designed to measure the FLT flare effect) and will go on to the 
3rd scheduled FLT-PET/CT scan (designed to measure changes in tumor proliferation). If 
the 2nd FLT PET/CT scan is omitted the reason (e.g. scheduling limitations) will be 
documented in the CRF, this will not be considered a protocol deviation. The third FLT-
PET/CT will be obtained at least 2 weeks following the start of the chosen cycle of therapy 
patients to assess for more distal effects of therapy on tumor proliferation.  
 
For each PET scan static images from the skull base to upper thighs will be acquired 
approximately 60 minutes after infusion of [18F] FLT.  Imaging data will be processed as per 
standard protocol. The SUVmax and total uptake volume of the primary tumor will be 
calculated FLT-PET/CT scans. Comparison will also be made between the initial tumor 
uptake (SUV) and Ki-67 staining of the tumor nuclei which will be performed by the 
Pathology Core at the CHOP Research Institute when biopsy tissue is available.  
 
The patient's active participation in this study will end following the completion of the last 
FLT-PET/CT scan. The patient's medical records will be accessed following for an 
estimated duration of 5-7 years following enrollment. This includes time for patient 
enrollment and clinical data collection. The patient’s clinical information will be accessed 
from the HUP clinical charts, HUP clinical database, including Medview, and radiology 
databases in order to calculate time-to-progression and overall survival. For those whose 
are cared for by a non-HUP clinician during this period, this clinician will be contacted by 
phone for follow-up. The patients may also be contacted by phone for follow-up. 
 
3.2 Study Design Exceptions: A study exception is a one time, intentional action or 
process that departs from the IRB and CTSRMC approved study protocol, intended for one 
occurrence. If the action disrupts the study progress, such that the study design or outcome 
(endpoints) may be compromised, or the action compromises the safety and welfare of 
study subjects, advance documented IRB and DSMC approval is required. For this in-
house study with a Sponsor Monitor, approval will be obtained from the Study Sponsor prior 
to submitting the exception request to the IRB and DSMC. 
 
3.3 Study Design Deviation: A study design deviation is a one time, unintentional action or 
process that departs from the IRB and DSMC approved study protocol, involving one 
incident and identified retrospectively, after the event occurred. If the impact on the protocol 
disrupts the study design, may affect the outcome (endpoints) or compromises the safety 
and welfare of the subjects, the deviation will be reported to the DSMC within 5 business 
days and the IRB within 10 business days. 
 
4 Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
1. Adult patients, at least 18 years of age 
2. Histologically confirmed non-small cell lung cancer with at least one site of disease > 1 
cm by at least one type of standard imaging (e.g. CT, chest x-ray, MRI) 
3. Recommmended to start systemic therapy which includes pemetrexed and a platinum-
based agent. 
4. Participants must be informed of the investigational nature of this study and provide 
written informed consent in accordance with institutional and federal guidelines prior to 
study-specific procedures. 


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5. Participants must be willing and able to comply with scheduled visits and imaging 
procedures in the opinion of the investigator or treating physician. 
4.2 
Exclusion Criteria 
1. Females who are pregnant or breast-feeding at the time of screening will not be eligible 
for this study. Female participants of child-bearing potential will have a urine pregnancy 
test at the time of the screening visit.  
2. Patients with only a single site of primary lung cancer who have undergone or are 
recommended to undergo radiation therapy to that site will not be eligible, the inclusion 
of patients who may be undergoing radiation therapy to ancillary disease sites may be 
allowed to enter the study at the discretion of the PI if it is not felt to affect the ability to 
capture FLT information for at least one primary site of disease. 
3. Patients who have undergone cancer surgery removing a significant portion of active 
disease, in the opinion of an investigator, within 2 months prior to study enrollment will 
be excluded. 
4. Inability to tolerate imaging procedures in the opinion of the investigator or treating 
physician 
5. Serious or unstable medical or psychological conditions that, in the opinion of the 
investigator would compromise the subject’s safety or successful participation in the 
study. 
6. Unwilling or unable to provide informed consent  
4.3 Subject Recruitment and Screening 
The patients will generally be offered enrollment at the time of their office visit to 
oncology at the Hospital of the University of Pennsylvania following determination of the 
line of therapy that is most appropriate. Study personnel or an investigator will present 
the patient with information regarding the study and enrollment. Enrollment into the study 
will be presented as optional and will not impact clinical management or choice of 
therapeutic intervention. It will be emphasized that enrollment in the study is not 
mandatory and that failure to enroll will not result in prejudice by the treating clinicians 
and will not affect patient care. 
 
All patients being considered for the study and eligible for screening must sign an 
informed consent for the study prior to any study specific procedures. Following 
completion of the pretreatment assessments and confirmation of eligibility, patients may 
undergo the baseline [18F]FLT PET/CT scan. 
 
4.4 Subject Withdrawal 
The criteria for enrollment must be followed explicitly.  If a subject who does not meet 
enrollment criteria is inadvertently enrolled, that subject should be discontinued from the 
study.  A subject may voluntarily discontinue participation in this study at any time.  The 
investigator may also, at his or her discretion, discontinue the subject from participating 
in this study at any time.  If a subject is prematurely discontinued from participation in the 
study for any reason, at any time, at either the investigator’s discretion or the subject’s 
request, an effort must be made to document the reason(s) why a subject fails to return 
to the study clinic for necessary visits or is discontinued from the study.  The primary 
reason for discontinuing participation in the study may include, but is not limited to, one 
of the following: 
 


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• 
Withdrawal of consent for treatment or imaging protocol by patient 
• 
Noncompliance with protocol, e.g., the patient fails to appear at one or more 
imaging procedures 
• 
Development of an intercurrent illness, injury, or medical condition likely to 
interfere with subject safety, the overall assessment, or the required 
administration of study medication 
• 
Pregnancy 
• 
Development of any condition for which the investigator feels treatment 
withdrawal is justified 
• 
Termination of the study  
Follow-up information will be obtained for subjects who discontinue the study.   
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety, 
behavioral, or administrative reasons. If a subject does not return for a scheduled visit, 
every effort should be made to contact the subject. In any circumstance, every effort 
should be made to document subject outcome, if possible.  
 
If the subject withdraws from the study, and also withdraws consent for disclosure of 
future information, no further evaluations should be performed, and no additional data 
should be collected. The sponsor may retain and continue to use any data collected 
before such withdrawal of consent. 
 
5 Investigational Agent 
5.1  Description 
3'-deoxy-3'-18F fluorothymidine ([18F]FLT) is a structural analog of the DNA 
nucleoside, thymidine. [18F]FLT is a radiolabeled imaging agent that has been proposed 
for investigating cellular proliferation with positron emission tomography (PET).  
Although [18F]FLT is not incorporated into DNA, it is phosphorylated by thymidine kinase, 
an intracellular enzyme of the proliferation pathway that is upregulated in proportion to 
DNA synthesis.  The phosphorylated, [18F]FLT is trapped in the cell.  Thus, FLT has 
potential as a marker of proliferating cells in proportion to the DNA synthesis rate.  
Therefore, [18F]FLT is proposed as a radiolabeled PET imaging probe for in vivo 
assessment of cellular proliferation in cancer. The drug is a clear solution that is stored 
at room temperature in a gray butyl septum sealed, sterile, pyrogen-free glass vial and 
has an expiration time of 8 hours.  The injectable dose of  [18F]FLT for most studies will 
be ≤ 0.07 mCi/kg of fluorine-18. In the dose of [18F]FLT, only a small fraction of the FLT 
molecules are radioactive.  The amount of injected drug is ≤ 6.1 µg (≤ 25 nmol per dose) 
of FLT. There is no evidence that nonradioactive and radioactive FLT molecules display 
different biochemical behavior.  
 
5.2 Preparation of Study Drug 
 


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The manufacturing of [18F]FLT will occur in the Cyclotron Facility of the Department of 
Radiology at the University of Pennsylvania.  This facility manufactures USP compliant 
radio-labeled compounds for human use on a daily basis.  The drug manufacturing will 
be fully documented and controlled by a set of Standard Operating Procedures (SOPs) 
prepared by the University of Pennsylvania Cyclotron under IND #102,482.  All standard 
hospital procedures will apply. 
5.3 Study Drug Receipt and Administration: [18F]FLT 
 
[18F]FLT will be delivered to the Nuclear Medicine Division of the University of 
Pennsylvania Medical Center by a trained Cyclotron team member in single dose vials 
according to the standard procedures outlined by the Cyclotron Facility.  Once the drug 
has been delivered to the Nuclear Medicine Division all standard hospital procedures will 
apply for handling, processing, and destruction of any residual amounts if applicable. 
Prescribed dose will be drawn and accurately measured by the dose calibrator in the 
imaging facility and immediately administered by bolus injection to the patient under the 
direct supervision of a Nuclear Medicine Authorized User .  The injectable dose of 
[18F]FLT for most studies will be approximately 5 mCi ± 20%.  In the dose of [18F]FLT, 
only a small fraction of the FLT molecules are radioactive.  [18F]FLT is administered to 
subjects by intravenous injection of ≤ 10 mL.  The injection will be followed by a saline 
flush. The infusion and imaging procedure will be terminated in any patient who exhibits 
anaphylaxis, significant dyspnea or chest pain. 
6 Study Procedures 
 
 
STUDY CALENDAR 
 
 
 
 
   
Pre- 
Study 
Day of      
[18F]FLT PET/CT 
(Baseline)2 
Day of [18F]FLT 
PET/CT  
(Scan 2)3 
Day of     
[18F]FLT  PET/CT 
(Scan 3)4 
Informed Consent 
X 
 
 
 
Demographics 
X 
 
 
 
Pregnancy Test1 
X 
X 
X 
X 
[18F]FLT Injection  
 
X 
X 
X 
Adverse Event Evaluation 
 
  X 5 
  X 5 
  X 5 
1A urine pregnancy test will be done at screening in all women of child-bearing potential. In addition, 
in patients that are unsure if they could be pregnant, a urine pregnancy test will be repeated before 
injection of FLT for females of childbearing potential on the day of the FLT-PET scan. 
2Baseline FLT PET/CT should take place no more than 1 week prior to initiation of the chosen cycle 
of therapy 
3Performed on the same day of initiation of either cycle 1 or 2 of systemic therapy, this scan is 
optional and may be omitted if it cannot be done on the day of therapy initiation  
4 Performed at least 2 weeks after initiation of the chosen cycle of therapy. 
5Follow up may occur by telephone or in person, depending on the subject’s schedule. Follow up 
should take place the next available business day after the FLT PET/CT scan (i.e. not a weekend 
or a holiday) 
 
 


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6.1 Initial pre-study screening prior to [18F]FLT PET/CT scan  
 
The investigator will provide for the protection of the subjects by following all applicable 
regulations.  These regulations are available upon request from the sponsor.  The 
sponsor and IRB must review the informed consent form used during the informed 
consent process, and it must be available for inspection.   
Before any procedures specified in this protocol are performed, a subject must: 
• 
Be informed of all pertinent aspects of the study and all elements of informed 
consent.  
• 
Be given time to ask questions and time to consider the decision to participate. 
• 
Voluntarily agree to participate in the study.  
• 
Sign and date an IRB/IEC-approved informed consent form..    
 
The following additional patient data will be obtained:  demographics, including gender, 
date of birth and race, histologic diagnosis, age at diagnosis, height and weight. 
Correlative pertinent imaging including CT, MRI, FDG PET/CT or bone scan may be 
reviewed. For patients referred from outside the University of Pennsylvania health 
system, patient records and biopsy material and imaging as necessary, will be reviewed 
to determine eligibility for the study.  For women of childbearing potential a urine  
pregnancy test will be performed at the screening visit. 
6.2  [18F]FLT PET/CT Imaging Visit 
   
The following procedures will be done at each imaging session 
• 
Weight will be recorded 
• 
Injection of [18F]FLT 
• 
Prior each FLT-PET/CT scan, female patients of child-bearing potential may have a 
urine pregnancy test if the patient is unsure about whether she might be pregnant. 
 
All women of child-bearing potential will be asked on the day of the PET/CT scan if they 
might be pregnant this is a standard question for all patients who will be undergoing 
PET/CT scans due to the radiation exposure associated with the scan. If the patient is 
unsure about whether she might be pregnant then a urine pregnancy test will be 
performed prior to the injection of [18F]FLT. The patient will be made comfortable in a 
preparatory room. Approximately 5 mCi ± 20% of [18F]FLT will be administered by bolus 
injection to the patient under the direct supervision of a Nuclear Medicine Authorized 
User. A lesser activity may be injected if, in the opinion of a nuclear medicine authorized 
user, complete imaging data could be generated.  Prior to positioning on the PET/CT 
scanner the patient will be allowed to urinate if necessary. 
 
All patients will undergo a skull base to mid-thigh PET/CT scan starting at approximately 
60 minutes after [18F]FLT injection. A brief low-dose CT scan will be acquired according 
to standard PET/CT imaging procedures, this is used for attenuation correction and 
anatomical localization of findings in the PET scan. This can be performed either before 
or after the PET transmission scan. There are no separate diagnostic CT scans 
performed as part of this research.  
 


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A second [18F]FLT PET/CT scan will be performed, when possible,  on the same day of 
the initiation of either the 1st or 2nd cycle of therapy for lung cancer.  This scan may not 
take place in all patients. 
 
A third [18F]FLT PET/CT scan will be performed at least 2 weeks after the initiation of the 
chosen cycle of therapy.  
 
Adverse events that are grade 3 or higher will be recorded for the period up to 10 hours 
post injection of the radiotracer. Research personnel will conduct follow up by telephone 
or in person, depending on the subject’s schedule. Follow up should take place the next 
available business day (i.e. not a weekend or a holiday).  
6.3 [18F]FLT PET/CT Image Analysis 
 
Static images will be reconstructed using standard procedure and analyzed by visual 
inspection and standardized uptake values (SUV) analysis. SUVmax will be recorded for 
an index lesion, usually a primary lung lesion, follow up scans will use the same index 
lesion to compare change in SUVmax from baseline.  
6.4 
Post-FLT-PET/CT Follow-up  
The patient will be asked to allow long term follow up for the duration of their cancer care. 
Follow up will primarily occur through review of HUP clinical charts, HUP clinical 
database, including Medview, and radiology databases in order to estimate time-to-
progression or death. For those whose are cared for by a non-HUP clinician during this 
period, this clinician will be contacted by phone for follow-up. The patients may also be 
contacted by phone for follow-up. 
7 Statistical Plan 
7.1 Sample Size Determination 
With n=20 subjects, a 95% exact confidence interval for the response rate will be as wide as 0.456 
if the response rate is 50% (10/20), or as narrow as 0.305 if the response rate is 10% (2/20).  We 
will test whether the mean SUVmax is the same in subjects who respond and those who do not.  
With 10 responses, a two-sample t test comparing the means with type I error rate 5% will have 
power at least 80% if the difference in means is at least 1.32 standard deviations (SDs).  If there are 
5 responders and 15 non-responders, the power will be at least 80% if the difference in means is at 
least 1.53 SDs. 
7.2 Statistical Methods 
 
This is a pilot study of the FLT radiotracer to image tumor proliferative response of cancer to 
therapeutic intervention. We will characterize and examine associations among the following 
variables of interest: max standard uptake value (SUVmax); total tumor uptake volume; Ki-67 
staining; progression-free survival (PFS, measured as time from treatment to the earlier of 
progression or death); and overall survival (OS, time from treatment to death).  Time-to-event 
variables will be measured from the time of initiation of treatment, and will be censored at the data of 
last follow-up. 
 
Due to the exploratory nature of this pilot study, we do not anticipate having power to detect 
significant associations unless effects are very large. For continuous uncensored measures, 


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estimates will include means, standard deviations, 95% confidence intervals, medians and inter-
quartile range, which will tabulated and graphed by classification variables of interest. We will 
estimate distributions of PFS and OS by the Kaplan-Meier curve.  We will tabulate descriptive 
statistics for all variables of interest, using the data to aid in the planning of a more rigorous 
subsequent hypothesis-driven trial. Associations among relevant variables will be explored through 
the use of Spearman’s correlation coefficient, bivariate plots, and the logrank test, as appropriate.  
We will conduct statistical analyses using STATA software.  
8 Safety and Adverse Events 
8.1 Definitions 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
• Unexpected in nature, severity, or frequency  (i.e. not described in study-related 
documents such as the IRB-approved protocol or consent form, the investigators 
brochure, etc) 
• Related or possibly related to participation in the research (i.e. possibly related 
means there is a reasonable possibility that the incident experience, or outcome 
may have been caused by the procedures involved in the research) 
• Suggests that the research places subjects or others at greater risk of harm 
(including physical, psychological, economic, or social harm). 
 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or 
worsens in severity during the course of the study.  Intercurrent illnesses or injuries 
should be regarded as adverse events.  Abnormal results of diagnostic procedures are 
considered to be adverse events if the abnormality: 
• results in study withdrawal 
• Is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is 
any AE that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are 
clearly of major clinical significance.   They may jeopardize the subject, and may require 
intervention to prevent one of the other serious outcomes noted above.  For example, 
drug overdose or abuse, a seizure that did not result in in-patient hospitalization, or 
intensive treatment of bronchospasm in an emergency department would typically be 
considered serious.  
 


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All adverse events that do not meet any of the criteria for serious should be regarded as 
non-serious adverse events.  
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as 
the period from the initiation of any study procedures to the end of the study treatment 
follow-up.  For this study, the study treatment follow-up is defined as 10 hours following 
the administration of the study radiotracer [18F]FLT.  
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting 
condition should be recorded as an adverse event if the frequency, intensity, or the 
character of the condition worsens during the study period. 
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained.  At 
the last scheduled visit, the investigator should instruct each subject to report any 
subsequent event(s) that the subject, or the subject’s personal physician, believes might 
reasonably be related to participation in this study.  The investigator should notify the 
study sponsor of any death or adverse event occurring at any time after a subject has 
discontinued or terminated study participation that may reasonably be related to this 
study.   
 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed 
otherwise in this protocol.  Any condition responsible for surgery should be documented 
as an adverse event if the condition meets the criteria for and adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported 
as an adverse event in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for a preexisting condition.  Surgery should not be reported as an 
outcome of an adverse event if the purpose of the surgery was elective or 
diagnostic and the outcome was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the 
study, unless it is a worsening or increase in frequency of hospital admissions as 
judged by the clinical investigator. 
8.2 Recording of Adverse Events 
At each FLT PET/CT imaging appointment, the investigator must seek information on 
adverse events specific to imaging procedures or injection of FLT by specific questioning 
and, as appropriate, by examination.  Information on all adverse events that are grade 3 
or higher should be recorded immediately in a source document or the medical record. 
All clearly related signs, symptoms, and abnormal diagnostic procedures results should 
recorded in the source document, though should be grouped under one diagnosis. 


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All adverse events occurring during the adverse event reporting period, 10 hours 
following injection of [18F]FLT must be recorded if they are grade 3 or higher.  The 
clinical course of each event should be followed until resolution, stabilization, or until it 
has been determined that the study treatment or participation is not the cause.  Serious 
adverse events that are still ongoing at the end of the adverse event reporting period 
must be followed up to determine the final outcome.  Any serious adverse event that 
occurs after the adverse event reporting period and is considered to be possibly related 
to the study treatment or study participation should be recorded and reported 
immediately. 
8.3 Reporting of Serious Adverse Events and Unanticipated Problems 
Investigators and the protocol sponsor must conform to the adverse event reporting 
timelines, formats and requirements of the various entities to which they are responsible, 
but at a minimum those events that must be reported are those that are: 
• related to study participation, 
• unexpected, and  
• serious or involve risks to subjects or others  
(see definitions, section 8.1).   
 
If the report is supplied as a narrative, the minimum necessary information to be 
provided at the time of the initial report includes: 
• 
Study identifier 
• 
Subject number 
• 
A description of the event 
• 
Date of onset 
• 
Current status 
• 
Whether study was discontinued 
• 
The reason why the event is classified as 
serious 
• 
Investigator assessment of the association 
between the event and study drug ([18F]FLT) 
 
8.3.1 Investigator reporting: notifying the study sponsor 
 
Any study-related unanticipated problem posing risk of harm to subjects or others, 
and any type of serious adverse event, must be reported initially  to the study 
sponsor (The Department of Radiology IND office) by email within 24 hours of 
when the investigator becomes aware of the event.  To report such events, a 
description and summary of the event must be completed by an investigator or 
designee, signed by the investigator and faxed or emailed to the study sponsor 
within 48 hours of when the investigator becomes aware of the event.  The 
investigator will keep a copy of this SAE summary report on file at the study site.  
Further information about follow up or resolution of serious adverse events should 
be provided promptly to the study sponsor as it is available and/or upon the 
request of the sponsor. 
8.3.2 Investigator reporting: notifying the Penn IRB 
This section describes the requirements for safety reporting by investigators who 
are Penn faculty, affiliated with a Penn research site, or otherwise responsible for 
safety reporting to the Penn IRB. The University of Pennsylvania IRB (Penn IRB) 
requires expedited reporting of those events related to study participation that are 


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unforeseen and indicate that participants or others are at increased risk of harm.  
The Penn IRB will not acknowledge safety reports or bulk adverse event 
submissions that do not meet the criteria outlined below.  The Penn IRB requires 
researchers to submit reports of the following problems within 10 working days 
from the time the investigator becomes aware of the event: 
 
• Any adverse event (regardless of whether the event is serious or non-
serious, on-site or off-site) that occurs any time during or after the research 
study, which in the opinion of the principal investigator is: 
Unexpected (An event is “unexpected” when its specificity and severity are 
not accurately reflected in the protocol-related documents, such as the IRB-
approved research protocol, any applicable investigator brochure, and the 
current IRB-approved informed consent document and other relevant 
sources of information, such as product labeling and package inserts.) 
AND 
Related to the research procedures (An event is “related to the research 
procedures” if in the opinion of the principal investigator or sponsor, the 
event was more likely than not to be caused by the research procedures.) 
 
Reporting Process 
Unanticipated problems posing risks to subjects or others as noted above 
will be reported to the Penn IRB using the form: “Unanticipated Problems 
Posing Risks to Subjects or Others Including Reportable Adverse Events” or 
as a written report of the event (including a description of the event with 
information regarding its fulfillment of the above criteria, follow-up/resolution 
and need for revision to consent form and/or other study documentation). 
 
Copies of each report and documentation of IRB notification and receipt will 
be kept in the Clinical Investigator’s study file. 
8.3.3 Investigator reporting: notifying the Cancer Center DSMC 
 
AEs will be graded according to Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 for reporting to the DSMC: 
• 
All grade 3 or higher events within five days of knowledge 
• 
All unexpected deaths within 24 hours of knowledge 
• 
All others deaths within 30 days of knowledge 
8.3.4 Sponsor reporting: Notifying the FDA 
The study sponsor is required to report certain study events in an expedited fashion to the FDA.  
These written notifications of adverse events are referred to as IND safety reports. The following 
describes the safety reporting requirements by timeline for reporting and associated type of 
event: 
 
• Within 7 calendar days 
Any study event that is: 
– associated with the use of the study drug 
– unexpected,  
– fatal or life-threatening, and  


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• Within 15 calendar days 
Any study event that is: 
– associated with the use of the study drug, 
– unexpected, and 
– serious, but not fatal or life-threatening 
-or- 
– a previous adverse event that was not initially deemed reportable but is later found to 
fit the criteria for reporting (reporting within 15 calendar days from when event was 
deemed reportable). 
Any finding from tests in laboratory animals that:  
– suggest a significant risk for human subjects including reports of mutagenicity, 
teratogenicity, or carcinogenicity. 
 
Additional reporting requirements 
Sponsors are also required to identify in IND safety reports all previous reports concerning 
similar adverse events and to analyze the significance of the current event in light of the 
previous reports. 
 
8.3.5 Sponsor reporting: Notifying participating investigators 
It is the responsibility of the study sponsor to notify all participating investigators, in a written 
IND safety report, of any adverse event associated with the use of the drug that is both serious 
and unexpected, as well as any finding from tests in laboratory animals that suggest a 
significant risk for human subjects.  Additionally, sponsors are also required to identify in IND 
safety reports all previous reports concerning similar adverse events and to analyze the 
significance of the current event in light of the previous reports. 
 
 
8.4 Medical Monitoring 
It is the responsibility of the Principal Investigator, Dr. Katz and the nuclear medicine 
AUs overseeing injection of the investigational agent, to oversee the safety of the study.  
This safety monitoring will include careful assessment and appropriate reporting of 
adverse events as noted above, as well as the construction and implementation of a site 
data and safety-monitoring plan (see section 11 Auditing, Monitoring and Inspecting).  
Medical monitoring will include a regular assessment of the number and type of serious 
adverse events. 
. 
9 Data Handling and Record Keeping 
9.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the 
following:  
• What protected health information (PHI) will be collected from subjects in this 
study 
• Who will have access to that information and why 


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• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization.  For subjects that have revoked authorization to collect or use PHI, 
attempts should be made to obtain permission to collect at least vital status (i.e. that the 
subject is alive). 
 
All research personnel associated with this study have completed the University of 
Pennsylvania’s Patient Oriented Research Training Program as well as HIPAA 
Compliance Training.  Trained staff will assess eligibility, introduce the study rationale, 
procedures, study risks, and collect the combined informed consent/HIPAA authorization 
form.  The study team will work to uphold the privacy of the participants in several ways.  
Communications made among study staff regarding participants will use ID numbers 
whenever possible and minimize the use of patient name or other identifying information 
except when necessary for conduct of the study. Paper-based records will be kept in a 
secure location and only be accessible to personnel involved in the study. Computer-
based files will only be made available to personnel involved in the study through the 
use of access privileges and passwords. Whenever feasible, identifiers will be removed 
from study-related information. In data analysis sets, we will use ID numbers and/or 
patient initials only.   
 
Precautions will be applied to protecting subject privacy and the protected health 
information detailed below: 
 
1. Name 
2. Address 
3. Date of Birth 
4. Telephone Number 
5. Email address 
6. Emergency contact number, name, and relationship 
7. Medical Record Number 
8. Health Plan ID numbers 
 
Data will be accessible to the study investigators, all study staff, Department of 
Radiology IND office representatives, Radiation Research Safety Committee members, 
UPenn IRB and Office of Human Research, and the FDA (if desired).   
9.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source 
data are contained in source documents.  Examples of these original documents, and data 
records include: hospital records, clinical and office charts, laboratory notes, memoranda, 
subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded data from 
automated instruments, copies or transcriptions certified after verification as being accurate and 
complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject 
files, and records kept at the pharmacy, at the laboratories, and at medico-technical 
departments involved in the clinical trial. 


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9.3 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study.  All 
data requested on the CRF must be recorded.  All missing data must be explained.  If a space 
on the CRF is left blank because the procedure was not done or the question was not asked, 
write “N/D”.  If the item is not applicable to the individual case, write “N/A”.  All entries should be 
printed legibly in black or blue ink.  If any entry error has been made, to correct such an error, a 
single straight line will be drawn through the incorrect entry and correct data entered above it.  
All such changes will be initialed and dated.   For clarification of illegible or uncertain entries, the 
clarification will be printed above the item, then the item will be initialed and dated. 
9.4 Records Retention 
The investigator will retain study essential documents for at least 2 years after the last approval 
of a marketing application in their country and until there are no pending or contemplated 
marketing applications in the USA or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  These documents should 
be retained for a longer period if required by an agreement with the sponsor.  In such an 
instance, it is the responsibility of the sponsor to inform the investigator/institution as to when 
these documents no longer need to be retained.  
 
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
The Principal Investigator is responsible for assigning staff for preliminary monitoring of study 
files.  Staff members are required to review all subject binders for completion and accuracy. 
This review will be documented.  The investigative team will meet after Subject 1 to review the 
study flow and to discuss any issues that occurred.  The study team will also determine at this 
time if any modifications to the protocol are necessary.  This meeting will be documented.   The 
Sponsor will also supply a Departmental monitor (assigned through the Departmental IND 
office),  and DOD medical monitor, Daniel Pryma, MD, for the below plan.  
 
The role and responsibilities of the Departmental Research Monitor listed in the protocol 
include: 
a)  May discuss the protocol with the investigators and consult with others outside the 
study about the research. 
 
b)  Shall report to the Sponsor who will then be obligated to ensure the Principal 
Investigator properly reports to the IRB, the Abramson Cancer Center CTSRMC 
(Clinical Trials Scientific Review and Monitoring Committee). Study monitoring 
ensures that necessary steps are taken to protect the safety and well-being of 
subjects. 
 
c) The study Departmental Research monitor (on behalf of the Sponsor) will ensure 
that the Principal Investigator communicates with the UPENN IRB and CTSRMC in 
accordance with the reporting structure of those entities in the case of a Serious 
Adverse Event (SAE). The study Departmental Research monitor will ensure the final 
determination is properly documented and reported to all necessary regulatory bodies 
as well as the USAMRMC ORP HROP.  
 
d) The study Departmental Research monitor will assist the Principal Investigator if 
needed to ensure all SAE’s are properly documented. This will including reviewing all 


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reports if request, on behalf of the Sponsor prior to submitting to the regulatory 
committees (IRB, CRSRMC).  
e)  The study Departmental Research monitor or will assist with communication 
between the Sponsor and the Principal Investigator as needed.   
 
The role and responsibilities of the study DOD Medical Research Monitor listed in the protocol 
include: 
 
a)  May discuss the protocol with the investigators, interview subjects, and consult with 
others outside the study about the research. 
 
b)  Shall have the authority to stop the protocol, remove subjects from the protocol, and 
take any necessary steps to protect the safety and well-being of subjects until the IRB can 
assess the Monitor's report. 
 
c)  Shall have the responsibility to promptly report their observations and findings to the 
IRB or other designated official if in disagreement with the assessment of the PI. 
 
d)  Is required to review all unanticipated problems involving risks to subjects or others, 
serious adverse events and all subject deaths associated with the protocol and provide an 
unbiased written report of the event. At a minimum, the research monitor must comment 
on the outcomes of the event or problem and in the case of a serious adverse event or 
death, comment on the relationship to participation in the study.  
 
e)  The research monitor must also indicate whether he/she concurs with the details of the 
report provided by the principal investigator. Reports for events determined by either the 
investigator or research monitor to be possibly or definitely related to participation and 
report of events resulting in death must be promptly forwarded to the USAMRMC ORP 
HRPO. 
 
 
The investigator will allocate adequate time for such monitoring activities. The Investigator will 
also ensure that the monitor or other compliance or quality assurance reviewer is given access 
to all requested study-related documents and facilities if necessary. 
   Frequency 
Enrollment will be complete when up to 20 evaluable subjects are enrolled into the 
trial.   Monitoring sessions will be conducted periodically throughout the study as 
described below.   
 
• 
The first monitoring session will occur after the first two subjects have 
been enrolled. 
 
• 
A second monitoring session will be conducted when approximately 
50% of the subjects have been enrolled.   
 
• 
A third monitoring session will be conducted after 100% of the subjects 
have been enrolled.  This visit may be conducted after the subjects have 
completed the study and can also serve as the close-out monitoring visit. 
 
Data Review 
Case Report Forms (CRFs) for the first 2 subjects will be 100% source data verified.  
In addition, the CRFs for at least an additional 3 randomly selected subjects will be 
100% source data verified.   
 


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If a high error rate is noted during the data review, this monitoring plan may be revised 
and more subject files may be 100% source data verified  
 
Additional subjects/events to be reviewed: 
All subjects who discontinued due to serious adverse events will be reviewed for key 
safety and efficacy data.  
 
10.2 Regulatory Documents Reviewed 
The Regulatory Documents will be maintained in the Regulatory Binder and electronically.  The 
Regulatory Binder may be reviewed by the monitor during any visit.  The monitor will review the 
regulatory binder for completeness.    
10.3 Documentation of the Monitoring Visit 
Monitoring Report 
All monitoring visits will be documented on the Monitor’s Report and Visit Checklist.    The 
original report for each session will be filed in the Sponsor section of the Regulatory Binder. 
The Sponsor will also retain a copy of this report. 
 
 
10.4 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, the sponsor, 
government regulatory bodies, and University compliance and quality assurance groups of all study related 
documents (e.g. source documents, regulatory documents, data collection instruments, study data etc.).  
The investigator will ensure the capability for inspections of applicable study-related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
11 Ethical Considerations 
This study is to be conducted accordance with applicable US government regulations and 
international standards of Good Clinical Practice, and applicable institutional research policies 
and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent 
Ethics Committee (EC) or Institutional Review Board (IRB), in agreement with local legal 
prescriptions, for formal approval of the study conduct.  The decision of the EC/IRB concerning 
the conduct of the study will be made in writing to the investigator and a copy of this decision 
will be provided to the sponsor before commencement of this study.   
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study.  This consent form will be submitted with the protocol for review and approval by the 
EC/IRB for the study.  The formal consent of a subject, using the EC/IRB-approved consent 
form, must be obtained before that subject undergoes any study procedure.  The consent form 
must be signed by the subject or legally acceptable surrogate, and the investigator-designated 
research professional obtaining the consent.  
 


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sponsor 
Neither the complete nor any part of the results of the study carried out under this protocol, nor 
any of the information provided by the sponsor for the purposes of performing the study, will be 
published or passed on to any third party without the consent of the study sponsor.  Any 
investigator involved with this study is obligated to provide the sponsor with complete test 
results and all data derived from the study. 
 
12 Study Finances 
12.1 Funding Source 
This study will be funded through the Department of Radiology and through funds through 
currently funded NIH and DOD grants and pending grant applications. 
12.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the conflict 
reviewed by a properly constituted Conflict of Interest Committee with a Committee-sanctioned 
conflict management plan that has been reviewed and approved by the study sponsor prior to 
participation in this study.  All University of Pennsylvania investigators will follow the applicable 
University conflict of interest policies. 
12.3 Subject Stipends or Payments 
We will pay for the cost of parking, if not already covered through the hospital, on the day of 
each of the 2-3 PET/CT scans. In addition, we will reimburse the patient a maximum of $1000 
($50- completion of 1st scan, $50-completion of 2nd scan, $900- completion of 3rd scan) after the 
completion of the last FLT-PET/scan to cover the inconvenience of time and effort spent in 
participation of this study.  
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