A Pilot Study of 18F Fluorothymidine (FLT) PET/CT in Lymphoma
Phase: PHASE1
Conditions: Lymphoma
Sponsor: National Cancer Institute (NCI)

Version Date: March 08, 2013
Protocol Number(s): CTEP # 8333
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Version Date:
March 08, 2013
Protocol Number(s):
CTEP # 8333
CC#:
08-C-0200
Title of Study:
A pilot study of 18F fluorothymidine (FLT) PET/CT in 
lymphoma
Abbreviated Title: 
18F fluorothymidine (FLT) in lymphoma
Principal Investigator:Karen A. Kurdziel, M.D.
Molecular Imaging Program (MIP)/CCR/NCI
Building 10, Room 1B40
Bethesda, MD 20892
Tel: 301-402-3817
kurdziek@mail.nih.gov
Associate Investigators:
Peter L. Choyke, M.D.
Molecular Imaging Program (MIP)/CCR/ NCI 
Building 10, Room 1B40
Bethesda, MD 20892
Tel: 301-451-4220
pchoyke@nih.gov
Wyndham Wilson, M.D., Ph.D.
Metabolism Branch/CCR/NCI
Building 10, Room 4N115
Bethesda, MD 20892
Tel: 301-435-2415
wilsonw@mail.nih.gov
Maria Liza Lindenberg, MD, MIP, CCR/NCI
Building 10/ RMB3B403 
Bethesda, MD 20892
301-443-0604
lindenbergml@mail.nih.gov
Yolanda McKinney MIP/NCI
Molecular Imaging Program (MIP)/CCR/NCI
Building 10, Room B3B81
Bethesda, MD  20892-1182
Tel: 301- 443-6913
ymckinney@mail.nih.gov
Research Contact: 
Yolanda McKinney MIP/NCI
Molecular Imaging Program (MIP)/CCR/NCI
Building 10, Room B3B81
Bethesda, MD  20892-1182
Tel: 301- 443-6913

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ymckinney@mail.nih.gov
Statisticians:
David J. Venzon, Ph.D.
Statistician, Biostatistics and Data Management Section
CCR, NCI
6116 Executive Blvd, Room 702 MSC 8325
Bethesda, MD 20892-8325
Phone: 301-496-9502
venzond@mail.nih.gov
Lori E. Dodd, Ph.D*. (Primary statistician)
Biometric Research Branch/NCI
EPN - Exec Plaza North, 8140
6130 Exec Blvd 
Rockville, MD 20892
301.402.038
doddl@mail.nih.gov
* Indicates Associate Investigators who will not be involved in clinical decisions or 
Investigational Drug ordering.
Study Sponsor: CIP/NCI
IND number/name of investigational drug:
# 71,260 /3'-deoxy-3'-18F fluorothymidine (FLT)   
NCI Supplied Agent:
3'-deoxy-3'-18F fluorothymidine (FLT) (NSC 743, 144)
Participating Institution Information
This protocol includes the participation of an affiliate institution to facilitate patient imaging as 
authorized by the Principal Investigator and approved by the Cancer Therapy Evaluation 
Program.  The Principal Investigator will make all treatment decisions related to the protocol and 
these will be conveyed to the affiliated investigator.  The Principal Investigator is responsible for 
the research data and for the appropriate use of the study agent.  The affiliate investigator has 
obtained IRB approval to participate in this CTEP-sponsored trial.
Affiliated Institution:
Walter Reed National Military Medical Center (Nuclear Medicine 
Department)
Federal Wide Assurance Number (FWA) FWA00017749
Lead Site Investigator:
Andrew Keenan, MD
Title: Nuclear Medicine Physician
Address: WRNMMC, Building 9a, Room 1330
Phone Number: 301-319-2711
Email Address: Andrew.M.Keenan.civ@health.mil
IRB/Research Contacts:
Toby Perkins 
Title: Deputy Commander Education, training and research

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Address: WRNMMC, Building 17, Floor 3
Phone Number: 301-319-8994
Email Address: Toby.Perkins@med.navy.mil
Pharmacy Contact:
Robert Massey
Title: Radiopharmacist
Address: WRNMMC, Building 9a, Room 1324
Phone Number: 301-319-0504
Email Address: Robert.Massey.ctr@health.mil           
Research Tech: 
Miland Valencia 
Title: Floor Supervisor, Nuclear Medicine
Address: WRNMMC, Building 9a, Room 1601
Phone Number: 301-319-2731
Email Address: Miland.Valencia@med.navy.mil

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PRECIS
Background:
x
FLT PET/CT has been shown to correlate with the rate of cellular/tumor proliferation. 
x
The Imaging Subcommittee of the International Harmonization Project in Lymphoma 
recommends performing FDG PET at least 3 weeks, and preferably 6-8 weeks after 
chemotherapy or chemoimmunotherapy therapy and 8- 12 weeks after radiation or 
chemoradiation therapy due to high FDG accumulation in inflammatory tissues. 
x
FLT uptake in inflammatory lesions is less prominent than FDG and it is likely that FLT 
PET/CT can better differentiate inflammation from tumor.
x
FLT PET/CT imaging is expected to better differentiate between treatment induced 
inflammation and malignancy and should enable early prediction of therapeutic response.
x
FLT PET/CT imaging is expected to differentiate between residual inflammatory residual 
masses from residual malignancy and therefore guide appropriate treatment.
Primary Objectives:
x
To estimate the diagnostic accuracy of FLT PET/CT as an early indicator of complete 
response to therapy in B and T cell lymphoma.
x
To estimate the diagnostic accuracy of FLT PET/CT in the evaluation of residual 
masses after therapy.
Eligibility:
x
Participant must be enrolled in a lymphoma therapy study at the NIH Clinical Center OR 
be enrolled in the CALGB 50303 study at another site OR undergoing a new course of 
treatment of lymphoma at another facility. The NCI Laboratory of Pathology will
confirm diagnosis for subjects enrolled at all CALGB study sites.
x
Participants must have a clinical course consistent with lymphoma and have available 
documentation of lymphoma from either the NCI or from an outside pathology 
laboratory.
x
Subjects enrolling in the early response arm must undergo baseline FLT PET prior to 
receiving a new course of lymphoma therapy.
x
Subjects enrolling in the residual mass evaluation arm can be enrolled at the time the 
FDG avid residual mass is discovered (i.e. no pre-therapy FLT image is required).
x
Subjects can enroll in both arms of the study.
x
Participant must be 18 years or older.
x
ECOG Performance score  of 0 or 1
x
SGOT, SGPT <5x ULN
x
ELOLUXELQ[8/1
Design:
x
There are 2 arms in this study
o
The first arm will assess FLT as an early predictor of tumor response to therapy
(treatment naive or recurrent disease). Subjects are imaged with FLT and FDG 
PET pre-therapy, following 2 cycles of therapy and post therapy.
o
The second arm will assess lymphoma patients with FDG PET positive residual 
mass. Subjects are imaged with FLT PET prior to standard of care biopsy of 
residual mass. If initial FDG PET data is not available in DICOM format or is of 

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suboptimal image quality, a repeat FDG PET/CT at the study site may be 
required.
x
We will accrue 70 participants (40 in the early response arm and 30 in the residual mass 
arm) to this study. 
Study Schema
Early response arm
*Complete response as defined by the Cheson revised response criteria and FDG PET/CT
Imaging Subcommittee of the International Harmonization Project in Lymphoma
Residual FDG PET positive residual mass arm
Confirm
Eligibility
Perform FLT 
PET/CT
Biopsy residual 
mass/medical f/u 
(standard of care)
Compare with 
pathology 
results
Patient referred and
identified as candidate 
Confirm
Eligibility
FLT and 
FDG 
PET/CT
2 cycles
of 
therapy
Post therapy 
FLT and FDG PET/CT
Compare 
FLT with 
response*
FLT and
FDG
PET/CT

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TABLE of CONTENTS
PRECIS........................................................................................................................................... 4 
1 
INTRODUCTION .................................................................................................................. 8 
1.1 
Objectives.....................................................................................................................................................8 
1.2 
Background ..................................................................................................................................................8 
1.3 
FDG PET for Response Assessment of Lymphoma at the Conclusion of Therapy.....................................9 
1.4 
FDG PET for Response Assessment of Early Treatment Response...........................................................10 
1.5 
FLT scanning for early response to therapy...............................................................................................12 
1.6 
FLT PET imaging compared with FDG PET imaging...............................................................................12 
1.7 
Findings as of March 1, 2013:....................................................................................................................13 
2 
Rationale ............................................................................................................................... 14 
3 
Imaging Agent Information .................................................................................................. 14 
3.1 
Pharmacology and Toxicology...................................................................................................................14 
3.2 
Toxicity of FLT in Humans .......................................................................................................................14 
3.3 
Dosimetry...................................................................................................................................................15 
3.4 
Previous human [18F]FLT imaging studies ................................................................................................16 
3.5 
Reported Adverse Events and Potential Risks ...........................................................................................20 
3.6 
[18F]FLT Administered Dose .....................................................................................................................20 
3.7 
Agent Availability......................................................................................................................................20 
4 
Eligibility assessment and enrollment .................................................................................. 20 
4.1 
Eligibility Criteria ......................................................................................................................................20 
4.2 
Registration Process...................................................................................................................................21 
5 
Study implementation........................................................................................................... 22 
5.1 
Overall Trial Design...................................................................................................................................22 
5.2 
[18F]FLT PET/CT imaging.........................................................................................................................23 
5.3 
Pathology (residual mass arm only) ...........................................................................................................23 
5.4 
Treatment modifications ............................................................................................................................24 
5.5 
Imaging Interpretation................................................................................................................................24 
6 
Protocol evaluations.............................................................................................................. 26 
6.1 
Study Calendar...........................................................................................................................................26 
6.2 
Concurrent Therapies.................................................................................................................................27 
6.3 
Surgical Guidelines....................................................................................................................................27 
6.4 
Radiation Therapy Guidelines....................................................................................................................27 
6.5 
Supportive care guidelines .........................................................................................................................27 
6.6 
Off Study Criteria.......................................................................................................................................27 
7 
Data collection and evaluation.............................................................................................. 28 
7.1 
Data collection ...........................................................................................................................................28 
7.2 
Response Criteria:......................................................................................................................................29 
8 
Statistical Section.................................................................................................................. 29 
8.1 
Objectives...................................................................................................................................................29 
8.2 
Data and Safety Monitoring Plan (DSMP).................................................................................................31 
9 
Human subjects protection.................................................................................................... 31 
9.1 
Rationale for Subject Selection..................................................................................................................31 
9.2 
Participation of Children............................................................................................................................31 
9.3 
Evaluation of Benefits and Risks/Discomforts...........................................................................................31 
9.4 
Risks/Benefits Analysis .............................................................................................................................32 
9.5 
Consent and Assent Process and Documentation.......................................................................................32 
10 Data reporting ....................................................................................................................... 32 
10.1 
Patient registration form.............................................................................................................................32 
10.2 
Data submission .........................................................................................................................................32 
10.3 
CTEP Multicenter Guidelines ....................................................................................................................32 
10.4 
Safety reporting..........................................................................................................................................33 

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10.5 
NCI-IRB Reporting....................................................................................................................................39 
10.6 
NCI Guidance for Reporting Expedited Adverse Events for Multi-Center Trials .....................................39 
11 Pharmaceutical information.................................................................................................. 40 
11.1 
[18F]FLT (IND # 71,260)..........................................................................................................................40 
12 References............................................................................................................................. 41 
13 APPENDIX A:  CTEP MULTICENTER GUIDELINES.................................................... 48 
13.1 
Responsibility of the Protocol Chair ..........................................................................................................48 
13.2 
Responsibilities of the Coordinating Center ..............................................................................................48 
13.3 
Agent Ordering ..........................................................................................................................................48 
14 Appendix B: Participating Site Expedited Event Report Form ............................................ 50 
15 Appendix C: Model Informed Consent Document (Residual Mass).................................... 54 
16 Appendix D: Model Informed Consent Document (Early Response).................................. 60 

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1
INTRODUCTION
1.1
Objectives
1.1.1
Primary Objectives
x
To estimate the diagnostic accuracy of FLT PET/CT as an early indicator of complete 
response to therapy in B and T cell lymphoma.
x
To estimate the diagnostic accuracy of FLT PET/CT in the evaluation of residual 
masses after therapy.
1.1.2
Secondary Objectives
x
To compare the diagnostic accuracy of FLT PET/CT with that of FDG PET/CT  as 
indicators of tumor response to therapy
x
To evaluate whether FLT tumor uptake either prior to therapy and/or following 
completion of therapy are in dependent predictors of complete response to therapy 
x
To evaluate whether there is a significant difference in tumor, selected normal organs 
,and mediastinal blood pool FLT dynamic influx parameter (Ki),SUV at 1 hours and 
2 hours post injection
x
To estimate the diagnostic accuracy of percent change in SUV between pre-treatment 
and mid-treatment FLT PET/CT as an indicator of complete response to therapy 
1.2
Background 
Malignant lymphomas are the fifth most frequently occurring type of cancer in the United States 
accounting for approximately 5 % of all malignancies. In 2007, it is estimated that 8,190 new 
cases of Hodgkin’s lymphoma (HL) and 63,190 new cases of non-Hodgkin’s lymphoma (NHL) 
will be diagnosed.(1, 2)
The appropriate management of lymphomas greatly depends on an accurate staging and 
evaluation of histologic features.(3, 4) For a long time, CT has been the imaging gold standard 
for the staging of lymphomas but offers only structural information. CT has excellent resolution;
however, disease is frequently assessed on the basis of size criteria. For example, lymph nodes 
less than 1 cm in diameter are not considered abnormal by most current criteria.(5, 6) In addition, 
CT may demonstrate residual masses on follow-up that represent fibrosis rather than active 
disease. Therefore, while computed tomography remains a valuable imaging method for the 
assessment of disease status, it provides no understanding of the metabolic or functional 
parameters of the disease. 
Nuclear medicine techniques permit the evaluation of functional status, and nuclear medicine is 
likely to have its greatest impact in the detection of viable tumor in persistent masses. Nuclear 
imaging can be conducted using single photon agents, such as 67Ga-citrate with SPECT (single 
photon emission computed tomography),(7, 8) or with positron emitters, such as 18F-
fluorodeoxyglucose (FDG) with PET (positron emission tomography). 
In comparison with 67Ga, 18F-FDG PET has proved to be far superior in the assessment of 
disease status and evaluation of the efficacy of different treatment modalities (9-11). PET has 
better resolution and is especially more accurate for detection of disease below the diaphragm. 
The basic principle of 18F-FDG imaging is based on Warburg's observation that the increased 
metabolic demands of rapidly dividing tumor cells required adenosine triphosphate generated by 

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glycolysis.(12) FDG is actively transported into cells and converted into FDG-6-phosphate by 
hexokinase. FDG-6-phosphate, because it is not a substrate for the enzyme responsible for the 
next step in glycolysis, is then trapped in the cell.
In 2001, the first commercial PET/CT was introduced combining the ability to assess function 
and anatomy in a single study (13-15) . A preliminary study(16) to evaluate 18F-FDG PET/CT 
versus CT and PET performed separately in patients with lymphoma showed an incremental 
improvement, with patient-based sensitivities of 78%, 86%, and 93% and region-based 
sensitivities of 61%, 78%, and 96% for CT, PET, and PET/CT, respectively. The patient-based 
specificities were 54%, 100% and 100% for CT, PET, and PET/CT, respectively. Whereas the 
region-based specificities were 89%, 98%, and 99%. Another study(17) showed PET/CT to be 
more accurate for staging (93%) than was PET alone (84%), with discordant image interpretation 
between PET and PET/CT in approximately 10% of patients.
1.3
FDG PET for Response Assessment of Lymphoma at the Conclusion of Therapy
Numerous studies have demonstrated the value of [18F]FDG PET and PET/CT for response 
assessment of lymphomas at the conclusion of front-line, salvage, or high-dose therapy(2, 18-
26). Based on the meta-analysis by Zijlstra et al(18), pooled sensitivityand specificity of FDG-
PET for detection of residual disease after completion of first-line therapy were 84% (95% CI, 
71% to 92%) and 90% (95% CI, 84% to 94%), respectively, for Hodgkin’s lymphoma (HL), and 
72% (95% CI, 61% to 82%) and 100% (95% CI, 97% to 100%), respectively, for aggressive 
Non-Hodgkin’s lymphoma (NHL). Accurate information regarding tumor status after treatment 
of these lymphoma subtypes is critical because these are curable malignancies.
The value of [18F]FDG PET in this setting is its ability to distinguish between viable tumor and
necrosis or fibrosis in residual masses. Conventional anatomic imaging modalities frequently are 
unable to make this distinction because the morphologic features of these tissues are usually 
indistinguishable (Figure 1 and Figure 2). Moreover, biopsy of a specific site may not be 
representative of disease activity since areas of necrosis/fibrosis might be interspersed among 
areas of viable tumor (Figure 3).
Figure 1 CT scan of the abdomen prior to chemotherapy demonstrating a large mesenteric mass consistent with 
biopsy proven lymphoma.

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Figure 2 CT scan after chemotherapy demonstrating a decrease in size of the mass but without biopsy, it is 
impossible to know if there is complete response to treatment.
Figure 3[18F] FDG PET scan after chemotherapy demonstrating the residual mesenteric mass with a central 
area of viable tumor. Even if a needle biopsy were performed there was a good chance of missing the viable 
tissue.
1.4
FDG PET for Response Assessment of Early Treatment Response
Less than half of all patients with aggressive NHL are cured with standard chemotherapy. 
[18F]FDG PET or PET/CT scanning during treatment of patients with HL and aggressive NHL 
may be justified as an early indicator of treatment efficacy as the information provided might be 
used to alter patient management and avoid unnecessary and ineffective chemotherapy. 
Changes in [18F]FDG uptake have been correlated with response to antitumor therapy by several 
authors (27-29). Several studies have also demonstrated a correlation between a visual 
normalization of [18F]FDG uptake as early as after one to four cycles of chemotherapyand 
patient outcome. In a study by Spaepen et al (25), 70 patients with newly diagnosed aggressive 
NHL were treated with doxorubicin-containing chemotherapy and underwent [18F]FDG PET 

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scan at mid-treatment. Presence or absence of abnormal [18F]FDG uptake was correlated with
progression-free survival (PFS) and overall survival (OS) (Figure 4 and Figure 5). Of the 37 
patients with a negative scan early during chemotherapy, 31 were still in complete remission 
(CR) after a median follow-up of 1107 days (range 595–1572). Thus, all patients who had a 
durable complete remission (CR-Cont) became FDG-negative after only three to four cycles of 
chemotherapy. Of 33 PET-positive cases early during chemotherapy, no patient maintained a 
durable complete response (CR-Cont) after completion of first line treatment. [18F]FDG-PET 
delineated patients who failed to achieve a complete response from other categories. Eight 
patients progressed during first-line therapy and all these patients died during further treatment 
(median OS 107 days; range 10–360). 15 patients achieved a partial response. During further 
treatment, nine of these 15 patients died of progressive disease, with a median OS of 333 days 
(range 74–1100). The other 6/15 patients had successful additional therapy and were 
momentarily in CR (median follow-up 1308 days; range 553–1500). The remaining 10 patients in 
this group achieved a complete response but subsequentlyrelapsed (CR-Rel) after a median PFS 
of 175 days (range 89–838) at the sites as seen on the interval PET scan.
Figure 4 Kaplan-Meir curve demonstrating differences of progression free survival in 33 patients with positive mid-
treatment [18F] FDG scan compared with 37 patients with negative mid-treatment FDG-PET scan (30)
Figure 5 Kaplan–Meier estimate of overall survival (OS) in 33 patients with a positive mid-treatment [18F] FDG 
scan compared with 37 patients with a negative mid-treatment FDG-PET scan (30)

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In another study, Kostakoglu et al(31) evaluated the predictive value of [18F]FDG-PET as an 
early response indicator after 1 cycle of chemotherapy for progression-free survival (PFS) in 
diffuse large cell lymphoma (DLCL) and classic Hodgkin disease (HD). Results demonstrated 
that all [18F]FDG PET negative patients after 1 cycle (n= 31) had sustained complete remission 
with a median follow-up of 28 months. Fourteen of sixteen PET positive patients after 1 cycle 
had refractory disease or relapsed (median PFS= 5.5 months). 
1.5
FLT scanning for early response to therapy
3'-deoxy-3'-18F fluorothymidine ([18F]FLT) is a structural analog of the DNA constituent, 
thymidine (Figure 6).  It 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 trapped in the cell due to phosphorylation by thymidine kinase, a 
part of the proliferation pathway.  As such, it has potential as a marker of proliferating tumor in 
proportion to the DNA synthesis rate. Therefore, [18F]FLT is proposed as a radiolabeled imaging 
probe for in vivo assessment of cellular proliferation in malignant tumors using PET.
One objective of this study is to evaluate the ability of [18F]FLT as an early predictor of 
treatment response and progression free survival.  Several studies evaluating the utility of FDG 
PET in the early assessment of tumor response have been performed; however, as FDG 
accumulates in inflammatory tissues as well as malignant tissues, differentiation between 
treatment induced tumor inflammation and tumor response becomes complicated.  Pre-clinical 
studies suggest that FLT PET can differentiate between inflammation and malignancy. These 
results are expected as FLT uptake is dependent on cellular proliferation, which is a less 
prominent feature of inflammation. 
FLT PET was recently successfully used to detect early response to chemotherapy in mice 
bearing a follicular lymphoma xenotransplant.(32) Another study by Hermann et. al. show that 
FLT PET imaging 2-7 days after completion of R-CHOP/CHOP  show a significant difference in 
mean SUV value between partial (2.6) and complete (1.5) responders. In one group of six 
subjects with high-grade non-Hodgkin’s lymphoma, the FLT SUV decreased 77% seven days 
after therapy with a total decrease in FLT SUV of 85% 40 days after therapy. In a study of breast 
cancer patients following 1 cycle of chemotherapy, the mean change in FLT SUV from baseline 
correlated with later (mean 5.8 months) changes in tumor marker (CA27.29).(33)
1.6
FLT PET imaging compared with FDG PET imaging
Even though [18F]FDG PET/CT imaging has revolutionized the modern management of 
lymphomas, [18F]FDG is not 100% specific for tumor cells and accumulation can be seen in
Figure 6(from the investigator’s brochure 1-03-05)
O
F
N
NH
HO
O
Me
O
O
OH
N
NH
HO
O
Me
O
Thymidine
FLT

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inflammation, apoptotic cells, granulomas, abscesses, and sarcoidosis (34-37). To overcome 
these problems several new radiotracers are currently under development. Recently, the 
thymidine analogue [18F]FLT has been suggested as an in-vivo marker of tumor’s proliferative 
activity and possible a more specific tumor imaging agent(38). An initial clinical trial comprising 
34 patients (39) indicated a significant correlation of [18F]FLT uptake in lymphoma and 
proliferation fraction in biopsied tissues as indicated by Ki-67 immunohistochemistry. In this 
particular study, patients were admitted for pre-therapeutic staging (25 patients) or restaging (9 
patients). [18F]FLT images were compared with routine staging which included clinical 
examination, laboratory screening, chest X-ray, CT of the chest and abdomen, and bone marrow 
biopsy. In 21 patients, [18F]FDG imaging was also performed. Data analysis demonstrated that 
[18F]FLT PET detected a total of 490 lesions compared with 420 lesions revealed by routine 
staging and the authors concluded that [18F]FLT PET may be suitable for imaging malignant 
lymphomas. 
In a study by Kasper et. al.(40), 48 patients with residual masses >2 cm were studies with FLT 
and FDG PET, 15 subjects were FDG + and 10 were FLT +. Two subjects who were FDG 
negative were FLT + and seven subjects who were FDG positive were FLT negative. 
Unfortunately they did not obtain pathologic confirmation of all subjects.  Another difficulty in 
evaluating this data lies in the selection of a 1.5 SUV cut-off for both FDG and FLT (normal 
background activity can have an SUV as high as 3 in some body regions).
Figure 7 Kaplan Meier plot of FDG and FLT positive mass versus FDG positive and FLT negative patients(40)
Even though these initial studies appear promising, the evaluation of residual masses after 
standard chemotherapy in lymphomas continues to present as a clinical dilemma. We therefore 
intend to investigate the ability of [18F]FLT PET to differentiate between residual viable tumor 
and non-viable masses after the conclusion of standard chemotherapy.  In this protocol we will 
include individuals with FDG positive residual masses to determine if they represent active 
disease based on biopsy or clinical follow-up.
1.7
Findings as of March 1, 2013:
To date, we have 22/30 patients in the residual mass arm and 8/40 patients in the early response
arm. After review of data we have noted that [18F]-FLT PET/CT appears to better differentiate 
viable lymphomatous masses from benign inflammatory processes than [18F]-FDG. This 

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suggests that in specific settings [18F]-FLT may help [18F]-FDG in predicting response to 
therapy. 
2
Rationale
FDG PET/CT has emerged as a powerful functional imaging tool for staging, restaging, and 
response assessment of lymphomas. In 2007, the American Society of Clinical Oncology, 
released new guidelines incorporating FDG PET in the evaluation of treatment response in non-
Hodgkin’s and Hodgkin’s lymphoma.(21) It is well known that FDG PET/CT imaging improves 
differentiation between viable and non-viable residual masses; however FDG accumulates in 
inflammatory lesions also, limiting its specificity.  FLT PET/CT, with uptake correlation with 
cellular proliferation, may serve as a more accurate predictor of early (intra therapy) therapy 
response and be more accurate than FDG PET/CT in differentiating between residual tumor and 
non-viable mass post therapy. 
3
Imaging Agent Information
3'-deoxy-3'-18F fluorothymidine (FLT)   
3.1
Pharmacology and Toxicology
FLT is a structural analog of the DNA constituent, thymidine. Thymidine has previously been 
labeled with C-11 for studies in cell culture and animals; results have shown that it is rapidly 
incorporated into newly synthesized DNA.(38) Radiolabelled thymidine has been used for 
noninvasive evaluation of tumor proliferation. Shields et al determined that [C-11] thymidine 
demonstrated a response to chemotherapy faster than 18F-FDG in 6 patients with 
malignancy.(38) However, because C-11 has a half-life of 20 minutes,(38) it is not practical for 
routine clinical use and other radiolabels are being investigated.  18F-FLT is radiolabelled with F-
18, which has a half-life of 110 minutes.(38)
The pharmacology of FLT is based on its action as an inhibitor of DNA synthesis.(41-43)
Intracellular metabolism of FLT produces nucleotides that inhibit endogenous DNA polymerases 
because they lack a 3'-hydroxyl substituent. This results in premature chain termination of DNA 
synthesis.(44, 45) These biochemical properties can account for FLT's prominent hematological 
and liver toxicity.(45-47) The pharmacology of FLT closely parallels that of the widely used 
prescription HIV-antiviral drug azidothymidine (AZT).(48, 49) Both FLT and AZT are 3'-
deoxythymidine analogs that act as inhibitors of DNA synthesis and are cleared from the body in 
the same way.  However, FLT is significantly more cytotoxic than AZT in test cell lines.(47)
Cellular uptake of FLT and thymidine is greater than that of AZT.  Transport of FLT and 
thymidine across cell membranes occurs by active transport and passive diffusion.(49)
3.2
Toxicity of FLT in Humans
FLT was investigated as an anti-AIDS drug in humans.(46) Toxic effects and death were 
reported for some subjects who received FLT during randomized concentration-controlled trials 
during a 16-week treatment of oral multi-dosing.  Doses of 0.125 mg/Kg every 12h produced a 
mean cumulated drug exposure (AUC12: area under curve) of 417 ng-h/mL.  At this level, 
serious (grade 3) hematologic toxicity occurred in 6 of 10 subjects.  At 300 ng-h/mL, grade 2 or 
greater (fall in hemoglobin to < 9.4 g/dL) developed within 4 weeks in 9 of 12 subjects.  At 200 
ng-h/mL almost no clinically significant anemia developed, but dose-limiting granulocytopenia 
(< 750 granulocytes/mm3) occurred in 5 of 15 subjects.  Mild peripheral neuropathy occurred in 

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2 of 10 subjects at 50 ng-h/mL, but was not dose-limiting.  FLT drug trials were terminated after 
the unexpected death of 2 subjects of hepatic failure.  One patient assigned to 200 ng-h/mL 
developed progressive liver failure and died after 12 weeks of FLT therapy.  A second subject,
who received a fixed dose of 10 mg/day, developed progressive liver failure and died at about 
the same time.  All surviving subjects were followed closely for 4 weeks after stopping FLT and 
none had evidence of clinically significant liver disease or other adverse effects. Overall, 25 of 
the 44 subjects receiving at least two doses of FLT completed the 16 week study without 
clinically significant adverse effects.
Unlabelled FLT was initially investigated as a treatment for HIV and AIDS, and toxicity studies
of the unlabeled compound have been performed at substantially higher doses than those 
proposed for imaging. Hematologic, hepatic and peripheral nerve toxicities were observed after 
administration of therapeutic doses (t 10 mg) of FLT for several weeks (See Section 3.1). In 
comparison, the proposed 18F-FLT PET studies use a maximum injection of 10Pg, a factor of 
1,000 times lower(50). The dose of FLT to be administered in this imaging trial is 1400-fold 
lower than the dose that led to serious toxicity in the studies described above.
3.3
Dosimetry
An [18F]FLT dose of 0.07 mCi/Kg with a maximum of 5 mCi was selected based on a prior 
human dosimetry study performed in 18 patients at the University of Washington(51). With this 
dose, the individual organ and total-body radiation dose associated with [18F]FLT is comparable to 
or lower than those reported for widely used clinical nuclear medicine procedures. There is ample 
preliminary evidence that a dose of 5 mCi is sufficient for imaging.  The actual dosing, 0.07 mCi/kg was 
determined by assuming average body weight of 70 Kg and dividing by the maximum total dose. As 
FLT is not lipid soluble, no upward adjustments are expected to be needed for subjects > 70 Kg. These 
details are specified in the IND. A summary of the relevant human dosimetry for 2 different 
voiding scenarios from the investigator’s brochure is included in Table 1.  For more details, the 
reader is referred to the IND.
Table 1 Human dosimetry estimates
Organ of 
Interest
Men       mGy/MBq   (mrad/mCi)
Women   mGy/MBq   (mrad/mCi)
Total Body Dose
Scenario 1     1.23E-02      (46) 
Scenario 2     1.26 E-02     (47)              
Scenario 1    1.56E-02        (58) 
Scenario 2    1.59 E-02       (59)                 
Bladder
Scenario 1     1.79E-01
(662)
Scenario 2     7.91E-02     (293) 
Scenario 1    1.74E-01       (646)
Scenario 2    7.76E-02       (287) 
Liver
Scenario 1     4.51E-02     (167)
Scenario 2     4.54 E-02    (168)
Scenario 1    6.42E-02       (238)
Scenario 2    6.45 E-02
(239)
Scenario 1:  Single bladder voiding at 6 h after [18F]FLT administration with a 10% post-voiding 
bladder residual decayed to infinity.  This scenario assumed no urine re-accumulation after 6 h. 
Scenario 2:  First bladder voiding at 2 h after [18F]FLT administration with a 10% post-voiding 
residual; urine re-accumulation between 2 and 6 h at a rate determined by the bladder curve fit; 
second bladder voiding at 6 h with a 10% post-voiding residual decayed to infinity.  This scenario 
assumed no urine re-accumulation after 6 h. 

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The first scenario is conservative, whereas the second has a more realistic voiding scheme.  
3.4
Previous human [18F]FLT imaging studies
Several preliminary studies using [18F]FLT imaging in human subjects have been performed in 
Germany and the United States (UCLA, University of Washington in Seattle, Wayne State 
University)(51-56).  The imaging protocols were pre-approved by their respective regulatory 
committees and conducted under the RDRC process, with patients receiving between 1.4 and 13 
mCi of [18F]FLT.  Some of the imaging results have been published (Table 2). The group in 
Seattle, which has the most experience with this agent in the US, has performed numerous 
studies in patients with lung cancer as well as a few in patients with primary brain tumors.  Their 
findings demonstrate the feasibility and merit of tumor imaging with [18F]FLT.  [18F]FLT PET 
showed increased uptake in tumor lesions outside the liver or bone marrow with standardized 
uptake values (SUV) of 4-7, enabling differentiation from surrounding tissues (SUV 0.5-2).

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Table 2 Summary of published manuscripts reporting  [18F]FLT human imaging studies
Year
Organ 
System
# of 
pts
mCi 
injected
MBq 
Injected
Specific 
Activity
nmole 
injected
Reference (#)
Previous 
Chemotherapy
Time post injection
2006
Brain
10
4
104-202
37-
222GBq/umol
N.C.
Yamamoto, 
2006 (57)
10 previous 
chemo
Dynamic 60 min; constant 
from 10-60min
2006
Lymphoma
34
9.3
265-370
Not reported
N.C.
Buck 2006 (39)
25 none, 9 
restaging
60 min
2006
Lung and 
SPN
22
5
185.2
Not reported
N.C.
Yap, 2006 (58)
none
60 min
2006
Breast
14
4
150
74 TBq/mmol
N.C.
Pio, 2006 (33)
Pre-,after 1-
cycle, and post-
chemo
Dynamic 45min 
2005
Brain
23
8.6
111-370
(321)
Not reported
N.C.
Jacobs,2005 
(59)
10 previous 
chemo
Dynamic 90min
2005
Esophageal
10
11.1
340-450
(410)
>10TBq/mmol
N.C.
vanWestreenen, 
2005 (60)
None
60 min
2005
Lung
47
9.5
265-370
Not reported
N.C.
Buck 2005 (61)
none
60 min
2005
Breast
10
390-420
(3 
patients)
>10TBq/mmol
N.C.
Been 2006 (62)
None
3 patients at 30,120,180, 
and 240 min; others at 120 
min
60-250 (7 
patients)
2005
Brain
25
4.7
141-218
(174)
~74 Bq/mmol
N.C.
Chen, 2005 
(63)
None
75: 11 patients
35:13 patients
(uptake peaks at 5- 10min)
2005
Brain
26
10
370
0.1-
0.3TBq/mmol
N.C.
Choi, 2005 (64)
None
60 min
2004
Lymphoma
7
4.3 -
13.2
Mean = 
324
Not reported
N.C.
Buchmann 
2004 (65)
Not reported
50-70 min

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Year
Organ 
System
# of 
pts
mCi 
injected
MBq 
Injected
Specific 
Activity
nmole 
injected
Reference (#)
Previous 
Chemotherapy
Time post injection
159 - 489
2004
Lung
17
5.7
Mean=210
>10TBq/mmol
40 nmol
Cobben 2004 
(66)
None
60 min
130-420
=10GBq/umol
2004
Lung
28
(a)
9
Mean=334
Not reported
N.C.
Halter 2004 
(67)
None
80-120min
265-370
2004
Breast
12
8.1-12.1
300-450
Not reported
N.C.
Smyczek-
Gargya 2004  
(68)
None
80-120 min
2004
Colorectal
18
9.7
360 + 25
Not reported
N.C.
Visvikis 2004 
(69)
Not reported
Dynamic 60 min
2004
HEENT
21
9.2
Mean=340
>10TBq/mmol
40 nmol
Cobben 2004 
(70)
Not reported
60 min
165-650
=10GBq/umol
2004
Soft Tissue
19
10.8
Mean=400
>10TBq/mmol
40 nmol
Cobben 2004 
(71)
Not reported
60 min
115 -430
=10GBq/umol
2003
Lymphoma
11
7.5
280
Not reported
N.C.
Wagner 2003 
(72)
Not reported
60 min
2003
Colorectal
10
(b)
9.5
351 + 52
Not reported
N.C.
Francis 2003 
(73)
Not reported
57+/-10 min
2003
Colorectal
17
(b)
9.4
Mean=360
Not reported
N.C.
Francis 2003 
(74)
Not reported
57-69 min
312-412
2003
Dosimetry 
(Lung)
18
5
185 MBq 
max
> 37 
GBq/umol
5 nmol
Vesselle 2003 
(75)
Not reported
2 hour dynamic
2003
Lung
16
5.4 -
10.8
200 - 400
Not reported
N.C.
Dittmann 2003 
(76)
None
114+/-20 min

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Year
Organ 
System
# of 
pts
mCi 
injected
MBq 
Injected
Specific 
Activity
nmole 
injected
Reference (#)
Previous 
Chemotherapy
Time post injection
2003
Melanoma
10
10.8
Med= 400
>10TBq/mmol
40nmol
Cobben 2003 
(77)
None
60 min
185-430
=10GBq/umol
2003
SPN
26
(c)
9
Mean=334
Not reported
N.C.
Buck 2003 (78)
None
45 min
265-370
2002
SPN
30
(c)
9
Mean=334
Not reported
N.C.
Buck 2002 (79)
None
45 min
265-370
2002
Lung
10
5
185 max
1Ci/umol =
5 nmol
Vesselle 2002 
(80)
None
2-hr dynamic
37GBq/umol
Total No. 
Subjects:
380*
N.C. = not calculated 
(a) There appear to be 10 additional unique patients who were not described in the Buck 2002 and 2003 manuscripts.
(b) It is unclear if the same patients are being described for both of the Francis manuscripts.
(c) It is unclear if the same patients are being described for both of the Buck, 2002 and 2003, manuscripts.
* Due to the possibility that the same patients are being described in some reports, the total # of unique patients studied in these published 
studies appears to be 198.

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As evidenced in Table 2, many of the published studies did not report the specific activity of the 
[18F]FLT, so it is not possible to determine the amount of FLT that was actually administered to 
the patient. Furthermore, none of the published studies addressed safety issues by describing 
laboratory results post injection or assessing for neurological sequelae such as mild peripheral 
neuropathy. 
3.5
Reported Adverse Events and Potential Risks
No adverse events have been reported for [18F]FLT at the dose to be used for this study. As 
described in Section 3.2, non-radioactive FLT has been investigated as an anti-AIDS drug, and 
some adverse effects, namely, reversible peripheral neuropathy, were observed in subjects 
exposed to 50 ng-h/mL plasma over a course of 16 weeks (15μg/kg q12h).  The FLT dose 
anticipated for this study will be <6.1μg for a single injection. Assuming a 70kg individual, the 
maximum concentration of FLT would be expected to be equivalent to 0.29 ng-h/mL.  The 
radiation exposure associated with this study is described in Section 3.6 and is comparable to the 
dose for other widely used clinical nuclear medicine procedures. 
3.6
[18F]FLT Administered Dose
The administered dose will be 0.07 mCi/kg with a maximum of 5 mCi.  The drug solution 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@)/7IRUPRVWVWXGLHVZLOOEH
mCi/kg of fluorine-18, not to exceed 5 mCi with a specific activity greater than 200 Ci/mmol at 
the time of injection.  In the dose of [18F]FLT, only a small fraction of the FLT molecules are 
radioactive.  The amount oILQMHFWHGGUXJLVJQPROSHUGRVHRI)/7>18F]FLT is 
DGPLQLVWHUHGWRVXEMHFWVE\LQWUDYHQRXVLQMHFWLRQRIP/7KHUHLVQRHYLGHQFHWKDW
nonradioactive and radioactive FLT molecules display different biochemical behavior.
3.7
Agent Availability
[18F]FLT will be provided by IBA, or Cardinal Health under an IND held by the Cancer Imaging 
Program (CIP)/NCI.
4
Eligibility assessment and enrollment
4.1
Eligibility Criteria
4.1.1
Inclusion Criteria
x
Participant must be enrolled in a lymphoma therapy study at the NIH Clinical Center OR 
be enrolled in the CALGB 50303 study at another site OR undergoing a new course of 
treatment of lymphoma at another facility.
x
Participants must have a clinical course consistent with lymphoma and have available 
documentation of lymphoma from either the NCI or from an outside pathology 
laboratory.
x
Participant must be 18 years or older
x
ECOG Performance score  of 0 or 1
x
Ability to provide informed consent. All patients must sign a document of informed 
consent indicating their understanding of the investigational nature and risks of the study 
before any protocol related studies are performed.
For subjects enrolling in early response arm
x
Must be enrolled in CALGB 50303 or a lymphoma therapy study at the NIH Clinical 
Center or undergoing a new course of treatment of lymphoma at another facility

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x
Must not have begun lymphoma therapy for this tumor occurrence/ relapse
x
Prior completed therapy does NOT affect eligibility 
For subjects enrolling in the residual FDG avid mass arm
x
Must have a residual FDG PET positive mass >1cm, with uptake greater than that of 
mediastinal blood pool (81)
x
Participant will undergo a repeat FDG PET/CT scan if the original FDG/PET imaging 
performed at an outside institution is not of adequate imaging quality for subjects 
enrolling in the residual FDG mass arm.
4.1.2
Exclusion Criteria
x
Known allergy to fluorothymidine 
x
Participants for whom enrollment would significantly delay (> 2 weeks) the scheduled 
standard of care therapy. 
x
Participants with any coexisting medical or psychiatric condition that is likely to interfere 
with study procedures and/or results are excluded
x
Participants with severe claustrophobia not relieved by oral anxiolytic medication or 
patients weighing >136 kg (weight limit for scanner table)
x
Other medical conditions deemed by the PI or associates to make the patient ineligible for 
protocol procedures.
4.1.3
Research eligibility evaluation (required within 2 weeks of each investigational 
agent (FLT) injection)
x
Liver enzymes: Should be completed within 14 days before injection of the 
radiopharmaceutical
x
SGOT, SGPT <5x ULN
x
ELOLUXELQ[8/1
x
Negative urine or serum HCG
4.2
Registration Process
4.2.1
NCI Patient Registration
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent.  A registration Eligibility Checklist from the web site 
(http://intranet.cancer.gov/ccr/welcome.htm) must be completed and faxed to 301-480-0757.
Verification of Registration will be forwarded electronically via e-mail to the research team. A 
recorder is available during non-working hours.
4.2.2
Patient Registration for Participating Site:
All patients must be registered through the NCI Central Registration Office (CRO). The CRO is 
open from 8:30am to 5:30pm EST Monday through Friday, excluding federal holidays.  A 
protocol registration form and cover memo will be supplied by the Coordinating Center, NCI 
CCR and updates will be provided as needed. Subject eligibility and demographic information is 
required for registration. To register a subject, send the completed registration checklist to 
Coordinating Center’s Research Nurse, Yolanda McKinney RN, 301-443-6913, and 
ymckinney@mail.nih.gov. Please indicate on the protocol registration form whether the patient 
is screening or is eligible to start treatment. The CRO will notify you either by e-mail or fax that 
the protocol registration form has been received. The CRO will assign a unique patient/subject 

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ID number for each subject that will be used to enter data into the C3D data base. Questions 
about eligibility should be directed to the Coordinating Center’s Research Nurse, Yolanda 
McKinney RN, 301-443-6913, and ymckinney@mail.nih.gov. Technical questions about the 
form should be directed to the Central Registration Office (301-402-1732).
5
Study implementation
5.1
Overall Trial Design
A member of the research team will perform the initial eligibility screening.
Informed consent will be obtained prior to the first FLT imaging study. If not obtained within 3 
weeks of scheduled FLT imaging, liver enzymes will be drawn.
5.1.1
For subjects enrolling in early response arm
x
Participants in this arm will undergo a pre-treatment FLT PET/CT and FDG PET/CT (+/-
2 weeks of each other) imaging prior to beginning lymphoma therapy.
x
They will then continue in a lymphoma therapy trial at the NIH Clinical Center or receive 
a new course of treatment at their home institution. 
x
Repeat FDG and FLT PET/CT studies will be performed following 2 cycles of 
chemotherapy.
o
The FDG PET/CT study should be performed as close as possible (i.e. within 4 
days) before the subsequent cycle; for example, on days 17 to 21 of a 21-day 
cycle.
o
The repeat FLT PET/CT imaging should be performed within +/- 2 weeks of the
FDG PET/CT study.  
x
Post treatment FDG and FLT PET/CT studies will be performed
o
The FDG PET/CT study will be performed >=3 weeks after the completion of 
chemotherapy
o
The FLT PET/CT scan will be performed within +/- one week of the 3rd FDG 
PET/CT.
x
Patients in this arm with residual FDG positive mass following completion of therapy 
may be enrolled in the residual mass arm.
x
The target lesion will be defined as the hypermetabolic (uptake > background)  lesion 
>1cm with the highest SUVmax at 1 hour post injection
x
Primary analyses will be performed on the target lesion and compared with complete 
response (CR or Cru, Table 6).
5.1.2
For subjects enrolling in the residual mass arm
Patients enrolled in an NIH Clinical Center lymphoma therapy protocol having a residual mass 
1 cm in longest dimension as measured by the CT component of the PET/CT with FDG uptake 
greater than that of mediastinal blood pool will undergo an FLT PET/CT within 2 weeks of the 
post treatment FDG PET/CT study. Patients on other lymphoma therapies from outside 
institutions, must have a FDG PET/CT positive mass >1cm, with uptake greater than that of 
mediastinal blood pool (81). Participant will undergo a repeat FDG PET/CT scan if the original 
FDG/PET imaging performed at an outside institution is not of “adequate imaging quality” for 
subjects enrolling in the residual FDG mass. The patient will undergo an FLT PET/CT within 2 

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weeks of the FDG PET/CT.  Patients will undergo clinically indicated biopsy of the residual 
mass after FLT PET/CT imaging. Fine needle aspiration (FNA) will be performed when biopsy 
is not possible. If a biopsy is not medically indicated, then the patient will be followed medically 
by the Lymphoma Team or by their outside oncologist.
The FLT SUV will be compared with pathological response, with the presence of any viable 
lymphoma cells on biopsy being considered positive for malignancy. For patients who do not 
undergo biopsy, the absence of tumor will be assessed by lack of lesion progression on routine 
medical follow-up. An FLT SUV greater than mediastinal background will be considered 
positive for malignancy.
5.2
[18F]FLT PET/CT imaging
5.2.1
Investigational agent 
[18F]FLT will be provided by IBA or Cardinal Health pharmacies.
5.2.1.1
Investigational agent administration:
The [18F]FLT will be brought by shielded carrier to the PET/CT scanner and will be injected 
intravenously over a 10-15 seconds period using an intravenous catheter under the supervision of 
an authorized user of radiopharmaceuticals.
Qualified staff or clinical research nurse will be in attendance during the infusion. In the event of 
an emergency such as an allergic response immediate treatment will be initiated using 
emergency medication kits available in the Nuclear Medicine/PET Departments.  If the 
participant requires admission due to the severity of the reaction, the participant will be admitted 
to the Lymphoma service for observation for the NCI site and the appropriate standard operating 
procedures should be followed for the participating site.
5.2.2
FLT PET/CT Imaging protocol
Immediately following the IV infusion of [18F]FLT, a dynamic 2D PET emission imaging with 
the target lesion in the field of view (FOV) will be performed for 60 minutes, immediately 
followed by a whole body static image.  An additional 2D PET emission imaging acquisition will 
be performed 120 minutes (+/- 10 minutes) post infusion.  A corresponding transmission CT will 
be acquired immediately before each emission scan.
5 ml of venous blood will be obtained ~1 hour and ~2 hours post injection to correct the 
measured F-18 counts for the % metabolized F-18 FLT.  The simplified TLC (thin layer 
chromatography) method described by Shields et. al.(82) will be performed to determine fraction 
of parent F-18 FLT remaining in the venous blood at those times. 
5.2.3
FDG PET/CT Imaging protocol
Standard image acquisition will be performed approximately 1 hour post injection of F18 FDG. 
5.3
Pathology (residual mass arm only)
In patients with FDG avid residual masses (uptake greater than mediastinal blood pool) who 
would routinely undergo biopsy or fine needle aspiration (FNA), the pathology results will be 
collected and compared with the corresponding FLT SUV. The presence of any viable 
lymphoma cells will be considered positive for residual malignancy. Biopsy is not medically 

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indicated in many patients undergoing therapy and therefore, determination of active disease will 
be based on clinical follow-up in those patients.
5.4
Treatment modifications
The expected dose of [18F]FLT is 5 mCi.  Due to potential unpredictable delays, the total dose 
administered may be reduced at the discretion of the PI.
5.5
Imaging Interpretation
[18F]FLT PET/CT
Figure 8 Kinetic model for [18F]FLT. k4 is assumed to be negligible at later time points. 
k1 and k2 are assumed to be equal, k3 is assumed to be the dominate factor in [18F]FLT 
accumulation in tumors over time.
Preliminary data suggests that [18F]FLT is essentially irreversibly phosphorylated and trapped 
inside cells (similar to [18F]FDG) during the imaging period.  Prior to this point, however, there 
is a flux of unphosphorylated [18F]FLT (reversible component).  If the rate of phosphorylation 
(k3) is low, then the early contribution of perfusion to the measured tumor activity is high. 
Assuming the phosphorylation rate correlates to the proliferative rate, a high rate of 
phosphorylation means that the cumulative measured tumor activity should be representative of 
cellular proliferation. The kinetics of FLT distribution has been evaluated in lung(53), brain(63,
83), colon(69) and other tumor types previously.(38, 54, 55) A comparison between the dynamic 
influx parameter (Patlak graphical analysis (below) and the standardized uptake values (SUV) at 
1 and 2 hours post injection will be made. 5cc venous blood samples will be obtained just prior 
to the 1 and 2 hour imaging sessions to measure for metabolites and measure blood radioactivity.
To improve the accuracy of the SUV measurements, the SUV values measured will be corrected 
for the fraction of non-metabolized FLT remaining in the blood at the time of image acquisition 
using thin layer chromatography estimation of metabolized fraction as described by Shield et. 
al.(82)
Blood
Cell
k1
k2
k4
k3
FLTfree
FLTPhos
FluxFLT=
3
2
3
1
k
k
k
k


FLTblood
)
(
dt
]
FLT
[
3
phos
t
FLT
k
d
free

 
phosphorylation rate

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5.5.1
Compartmental and Patlak(84-87) Graphical Analysis
A 3-compartment data analysis will be performed to estimate values for the rate constants and 
[18F] FLT flux parameters base on the model in Figure 4 and Figure 5.
The Patlak graphical method enables estimation of the influx rate constant (Ki) and the volume 
of distribution (Vd) of unphosphorylated [18F] FLT within the ROI from the data.  The plot of 
ROI activity/Plasma Activity vs. ³
vity
PlasmaActi
dt
vity
PlasmaActi
/)
*
(
will become linear for 
irreversible systems.  The slope of the linear portion is Ki and the y-intercept is Vd.  The primary 
assumptions of these estimations are that the uptake of tracer is irreversible and that exchange of 
[18F] FLT between the plasma and extracellular compartments has reached equilibrium.  The rate 
of clearance of [18F] FLT from the blood is equal to the Patlak influx rate constant (Ki) and is 
equal to k1k3/(k2+k3).
A plasma activity function (the input function) is classically obtained from the arterial blood 
samples.  Alternative methods of non-invasively deriving the plasma input function include ROIs 
drawn over the left atrial cavity (LA)/ basal portion of the left ventricular cavity (LV) or from a 
normalized population-based input function.  Because obtaining an arterial or venous input 
function would likely adversely effect patient enrollment, for this study an LV image derived 
input function will be used. (87-90)
5.5.2
General image parameter extraction
x
FLT and FDG uptake greater than surrounding background will be considered positive. 
x
The “target” will be identified, as a lesion >1cm with the highest SUV (amongst all 
identified hypermetobolic lesions).
x
All regions/volumes of interest will be saved as DICOM-RT structure sets. Region 
volumes, and SUV values will be output to an Excel spreadsheet using MIMVista 
imaging software (www.mimvista.com)
x
For the hypermetabolic lesions, an estimated smoothed maximum SUV (SUVmax) will be 
reported as the mean SUV value of an automated 85% maximum pixel value threshold 
based volume of interest (i.e. the average SUV of the “hottest” 15% of pixels in the user 
defined lesion).  This method reduces the chances of the SUVmax value being dominated 
one or more “noisy” pixel values.
x
All lesions will be followed from baseline with the same lesion number, even if they have 
resolved.
x
For quality control, mediastinal and left ventricular blood pool (BP) SUV means, spleen, 
and liver SUV mean will be measured in all FLT and FDG scans. 
o
To measure the left ventricular cavity BP SUVmean, the mean SUV of a 1 cm 
spherical volume of interest (VOI) will be placed in the left ventricular cavity, 
avoiding the myocardial wall
o
For liver and spleen SUVmean, a spherical VOI of 2 to 5 cm in diameter will be 
placed in a homogeneous area in the center of the organ (excluding the central 
hilum of the liver), and the mean SUV recorded.
x
For the FLT images, the Ki Patlak influx parameter will be extracted from the 60 minute 
dynamic data.  SUV values (corrected for the fraction of unmetabolized FLT (as 

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determined by thin layer chromatography (TLC)) will be recorded for the 1- and 2- hour 
static images.
o
For the primary analyses, the 1- hour SUV (SUV1) parameters will be used
x
For the FDG images SUV values will be recorded for the 1 hour static images.
x
On transmission CT, lesion dimensions will be determined in perpendicular planes where 
the lesion appears largest. 
5.5.3
Early response arm
x
The percent of decrease or increase in SUV uptake in post cycle 2 and end of treatment 
scans in comparison with baseline scans will be calculated as follow: 
SUVmax post cycle 2 or end of treatment – baseline SUVmax
----------------------------------------------------------------------------------------
Baseline SUVmax
Table 3 Image Analysis Parameters for Early Response Arm
Pre-treatment
Mid-treatment
Post Treatment
FLT (Ki, SUV1, SUV2)
FLT (Ki, SUV1, SUV2)
FLT (Ki, SUV1, SUV2)
FDG (SUV1)
FDG (SUV1)
FDG (SUV1)
CT (bidirectional 
measurements)
CT (bidirectional 
measurements)
CT (bidirectional 
measurements)
5.5.4
Residual mass arm
x
The size of the residual mass will be determined on CT and will include the entire length 
of the mass visible on CT (i.e. if only a portion of the mass is hypermetabolic, the 
anatomical size will be determined by the entire mass length, not just the portion which 
appears hypermetabolic)
x
The length used for the inclusion criteria is the longest measureable length
Table 4 Image Analysis Parameters for the Residual Mass arm
FLT (Ki, SUV1, SUV2)
FDG (SUV1)
CT (bidirectional measurements)
6
Protocol evaluations
6.1
Study Calendar
Table 5
Pre-study
Pre-therapy
(biopsy for the 
Residual Mass 
arm)
Post 2-cycles
End of study
Enroll in CALGB  50303
or other lymphoma 
therapy trial or undergoing 
a new course of treatment 
of lymphoma at another 
X

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Pre-study
Pre-therapy
(biopsy for the 
Residual Mass 
arm)
Post 2-cycles
End of study
facility
Informed Consent
X
Check Liver Function
X
X
X
X
Urine or Serum HCG
X
X
X
X
Early Response Arm
FDG PET/CT
X
Xc
X
X
FLT PET/CT
Xc
X
Xa
Residual Mass Arm
FDG PET/CT
Xb
FLT PET/CT
X
a.The FLT PET/CT scan will be performed at least 12 hours after, and +/- 2 weeks of, the FDG 
PET/CT study
b.If not performed at NIH or WRNMMC a repeat FDG PET/CT will be performed according to 
the prescribed FGD PET/CT protocol within 2 weeks of the FLT PET/CT study
c. Baseline FDG and FLT PETs must be performed prior to initiation of the current/new therapy 
in patients in the Early Response arm
6.2
Concurrent Therapies
No restrictions
6.3
Surgical Guidelines
FDG PET imaging must be performed >2 week following any surgical procedure to the target 
lesion.
6.4
Radiation Therapy Guidelines
In patients in whom the target lesion received radiation therapy, the FDG PET imaging must be 
performed >8 weeks following the completion of radiation therapy.
6.5
Supportive care guidelines
In the event that a patient has a reaction (allergic) to the contrast agent or radiotracer, all 
appropriate medical measures will be taken immediately.  In rare instances, this may entail 
admission to the hospital on the Medical Oncology (Inpatient Lymphoma) service for 
observation and the appropriate standard operating procedures should be followed for the 
participating site.
6.6
Off Study Criteria
Subjects will be enrolled in the study beginning with their consent for [18F]FLT imaging and 
ending following completion of all FLT PET/CT imaging.  Correlative clinical response data will 
also be obtained from data collected from the lymphoma therapy trial. 
Once a subject is taken off study, no further data can be collected, with the exception of follow-
up clinical data from the patients referring physicians. Patients will be taken off the study if:
x
Patient experiences an adverse event that prohibits them from completing the [18F]FLT
imaging sessions
x
Patients voluntarily withdraw from the study

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x
Patient completes all FLT PET/CT imaging 
x
Death
6.6.1
Directions for NCI 
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off-
study. An off-study form from the web site (http://intranet.cancer.gov/ccr/welcome.htm) main 
page must be completed and faxed to 301-480-0757.
6.6.2
Directions for participating site
All subjects must be registered through the NCI Central Registration Office (CRO). The CRO is 
open from 8:30am to 5:30pm EST Monday through Friday, excluding federal holidays.  An off-
study form will be supplied by the Coordinating Center, NCI CCR. Send the completed off-study 
form to the Coordinating Center’s Research Nurse; insert name, telephone number, and email.
7
Data collection and evaluation
7.1
Data collection
Demographic and summary data will be collected by research nurse or designee and entered in a 
password protected file in NCI C3D.  The data will be entered at least on a weekly basis.
Participating institutions will be trained in the use of NCI C3D and database access will be 
provided to site staff based on their designated duties.
The following is a list of specific data elements that will be collected or recorded in the database:
x
demographics, 
x
histological type and disease stage, 
x
diagnosis date 
x
history of previous therapy (including dates of therapy)
x
Date Informed Consent signed
x
ECOG Status
x
Labs
x
Radiotracer dose amount & time.
x
The following adverse events of any grade:
o
Localized discomfort at the IV injection site
o
Pain
o
Respiratory difficulties
o
Flushing
o
Dizziness
o
Itching/rash
o
Any other symptoms that could be secondary to an anaphylactic reaction
o
Any sign of illness or symptoms that appear or worsen after the F-18 FLT 
infusion
Imaging data will include storage of the images from each time point and intensity measurements 
from the tumor will be stored on a secure, password protected lab imaging database. Dr. Peter 
Choyke will serve as the study monitor responsible for the protocol.
The images will be stored on a secure database completely anonymized and administered by the 
Cancer Imaging Program, NCI. Access to these systems is restricted to authorized users.

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Please note that follow-up clinical data may be collected from the patients referring physicians. 
7.2
Response Criteria:
7.2.1
Early Treatment Arm
Overall response will be assessed according to the Cheson revised response criteria, 2007.(91).
This data will be collected under the therapy trial in which the patient is also enrolled. For 
primary analyses, CR and Cru will be considered positive for response.
Table 6 Summary of the response criteria
7.2.2
Residual Mass arm
The presence of viable lymphoma cells on biopsy/FNA or absence of lesion progression on 
medical follow-up will be considered positive for residual malignancy.
8
Statistical Section  
8.1
Objectives
8.1.1
Primary Objectives
x
1.a. To estimate the diagnostic accuracy of FLT PET/CT as an early indicator of 
complete response to therapy in B and T cell lymphoma.
x
1.b To estimate the diagnostic accuracy of FLT PET/CT in the evaluation of residual 
masses after therapy.
8.1.2
Secondary Objectives
x
2.a.To compare the diagnostic accuracy of FLT PET/CT with that of FDG PET/CT as an 
indicator of tumor response to therapy
x
2.b. To evaluate whether FLT tumor uptake prior to therapy or following completion of 
therapy are independent predictors of complete response to therapy
x
2.c. To evaluate whether there is a significant difference in tumor, selected normal organs 
,and mediastinal blood pool FLT dynamic influx parameter (Ki),SUV at 1 hours and 2 
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x
2.d To estimate the diagnostic accuracy of percent change in SUV between pre-treatment 
and mid-treatment FLT PET/CT with regard to complete response to therapy 
8.1.3
Analysis Plan
For the primary analyses, sensitivity and specificity will be estimated and 95% confidence 
intervals provided.  Subjects with an FLT SUV greater than mediastinal blood pool activity will 
be considered FLT positive. In the early response arm, subjects with complete response (CR or 
Cru, Table 6) as determined by the CHESON revised response criteria will be considered disease 
negative (all others will be considered disease positive). In the residual mass arm, subjects with 
any malignant cells on biopsy will be considered disease positive. 
For secondary objectives 2a and 2d, empirical ROC curves will be estimated, along with non-
parametric AUCs and corresponding 95% confidence intervals. For 2b, we will evaluate the 
ability of FLT to predict clinical response independent of other known predictors using logistic 
regression. For aim 2c, we will test for differences using signed-rank tests. 
No stratification based on lymphoma histology or treatment is planned due to the small amount 
of expected variability in treatments available.
8.1.4
Sample size
We plan to enroll 40 participants in the first arm and 30 participants in the residual tumor arm.  
In the first arm, we assume that patients enrolled in this trial come from a randomized trial of 
DA-EPOCH-R vs. R-CHOP.  With DA-EPOCH-R treatment, the expected response rate is 
74%(92), while with R-CHOP it is 50%. (21). If we assume half of the patients enrolled in this 
trial will receive DA-EPOCH-R and the other half will receive R-CHOP, the average response 
rate is 62%, which will provide about 25 responders, who will contribute to estimates of 
sensitivity. About 15 patients will be non-responders and will contribute to estimates of 
specificity.  The lower bounds for sensitivity are given in Table 7.  Lower bounds for specificity 
are given in Table 8.
For the second primary objective, we assume that the 50% of patients with FDG positive residual 
disease will have positive pathology.(93) This provides 15 positives and 15 negatives.  Table 8
provides lower bounds for confidence intervals for sensitivity and specificity for this objective.
The following table provides expected lower bounds for 95% confidence intervals given
observed values of sensitivity and specificity for a sample size of 15.We anticipate sensitivity 
and specificity to be about 85% and 90%, respectively. Hence, the sample size will provide 
lower bounds above the chance threshold of 50%.
Table 7
Sensitivity
(n=25)
Expected lower 
bound of exact 
95% CI
20/25(=.80)
0.59
21/25(=.84)
0.64
22/25(=.88)
0.69

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Table 8
Sensitivity/Specificity
(n=15)
Expected lower 
bound of exact 
95% CI
12/15 (=0.8)
0.52
13/15 (=0.87)
0.60
14/15 (=0.93)
0.68
8.2
Data and Safety Monitoring Plan (DSMP)
No adverse events are expected for the [18F]FLT PET/CT imaging study. The PI and research 
nurse will monitor the study for adverse events. Safety reporting will be performed as described 
in section 10.3. Should there be more than 3 instances of Grade 3 or greater toxicities that 
increase the risks to participants, the study will be suspended or closed depending on the severity 
of the adverse events. Due to the minimal risk of this study we will not have a formal DSMP, 
however, the PI and Study Chair will re-evaluate the protocol after each patient.
The images will be stored on a secure database completely anonymized and administered by the 
Cancer Imaging Program, NCI.  Access to these systems is restricted to authorized users.
Low level image analysis data and will be recorded in a password protected MS Access database 
on a secure server to allow for easy data manipulation.
9
Human subjects protection
9.1
Rationale for Subject Selection
All subjects must first be enrolled in a lymphoma treatment trial at the NIH Clinical Center OR 
be enrolled in the CALGB 50303 study at another site OR undergoing a new course of treatment 
of lymphoma at another facility. Both males and females will be eligible to enroll in this study.  
All ethnic groups/ race categories would be represented as they are represented in the disease as 
a whole.  Cognitively impaired individuals will not be included in this study, if they are unable to 
understand the informed consent.  Physically impaired persons who otherwise satisfy eligibility 
criteria will be included in this study.  
This study is considered more than minimal risk to subjects and offers NO direct benefit to 
individual subjects. Information gained from this study is expected to benefit future patients with 
lymphoma. We anticipate that a thorough discussion of the study at the time informed consent is 
obtained will minimize any susceptibility to undue influences and unnecessary risks as research 
subjects.
9.2
Participation of Children
Subjects must be 18 years of age or older.  Because no dosing or adverse event data are currently 
available on the use of FLT in patients <18 years of age, children are excluded from this study 
but will be eligible for future pediatric single-agent trials, if applicable.
9.3
Evaluation of Benefits and Risks/Discomforts
Risks and discomforts of the experimental procedure are expected to be small and related to the 
risks of [18F]FLT injection and PET/CT imaging.  Specific risks and potential complications will 
be clearly outlined in a separate consent form at the time of each procedure.  Most complications 
are expected to be minor and require no treatment. Risks and discomforts associated with 

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[18F]FLT PET imaging are discomfort of an IV placement and the theoretical effects of 
additional radiation exposure (ED estimated at 1.2 rads for each FLT PET/CT scan and 1.88 rads 
for the additional FDG PET/CT). The subject will be required to lay still on their back for back 
for up to 95 minutes for the longest scan.
9.4
Risks/Benefits Analysis
The risks of participation are minimal based on the tracer doses of FLT.  The benefits are 
similarly minimal as the participant is unlikely to derive any personal benefits.  However, the 
knowledge derived from the study could benefit future patients with similar clinical 
presentations.
9.5
Consent and Assent Process and Documentation
The subject will be informed of the study by a member of the research team. The subject will 
contact the study research staff who will explain the study in detail. A member of the research 
team will send the consent form and protocol (if requested) to the participant.  If the participant 
has any questions they will be answered by telephone.  A signed consent will be obtained on the 
day of the study.  The informed consent process will be documented in the patient’s medical 
record and on the informed consent document. This process will be performed by the local 
Principal Investigator or designee.
10 Data reporting
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0.
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means.  Reports are 
due January 31, April 30, July 31 and October 31.  Instructions for submitting data using the 
CDUS can be found on the CTEP web site (http://ctep.cancer.gov/reporting/cdus.html).
10.1 Patient registration form
See Sections 4.2.1 and 4.2.2.
10.2 Data submission
10.2.1 Clinical Data
The investigators will provide quarterly reports of clinical data on the C3D clinical trial software. 
Cumulative C3D will be submitted quarterly to CIP by electronic means. Reports are due 
January 31, April 30, July 31, and October 31.
10.2.2 Imaging Data
DICOM datasets (or digital datasets for non-DICOM studies) - of the PET, PET-CT and 
pertinent anatomic studies the patients undergo on the trial will be submitted quarterly to CIP via 
the NCIA (NCI Imaging Archive). The electronic transfer of image datasets is due January 31, 
April 30, July 31, and October 31.
Demographic information, correlative data and summary data will be entered into C3D weekly.
Data may be reported in laboratory publications as derived from pilot studies.  Patients will not 
be identified by name.
10.3 CTEP Multicenter Guidelines
This protocol will adhere to the policies and requirements of the CTEP Multicenter Guidelines.  
The specific responsibilities of the Principal Investigator and the Coordinating Center (Study

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Coordinator) and the procedures for auditing are presented in APPENDIX A:  CTEP 
MULTICENTER GUIDELINES.
The Principal Investigator/Coordinating Center is responsible for distributing all IND Action 
Letters or Safety Reports received from CTEP to all participating institutions for submission to 
their individual IRBs for action as required.
Except in very unusual circumstances, each participating institution will order DCTD-supplied 
agents directly from CTEP.  Agents may be ordered by a participating site only after the initial 
IRB approval for the site has been forwarded by the Coordinating Center to the CTEP PIO 
(PIO@ctep.nci.nih.gov) except for Group studies.
10.4 Safety reporting
10.4.1 Adverse Events
No adverse events have been reported for [18F]FLT at the strength to be used for this study. As 
described in Section 3.2, non-radioactive FLT has been investigated as an anti-AIDS drug, and 
some instances of reversible peripheral neuropathy were observed in subjects exposed to 50 ng-
h/mL plasma over a course of 16 weeks (15μg/kg q12h).  The FLT dose anticipated for this 
study will be <6.1μg for a single injection. Assuming a 70kg individual, the maximum 
concentration of FLT would be expected to be equivalent to 0.29 ng-h/mL.  The administration 
of a total 10-15 mCi of [F-18]FLT over several imaging time points required to assess the effects 
of therapeutic intervention (baseline and typically two time points during therapy) to humans 
poses a minimal risk for an adverse effect. Therefore, the risk profile for [F-18] FLT used as 
described in the Investigator’s Brochure consists of allergic reaction/anaphylaxis, which appears 
to be highly unlikely, and risks that would be associated with any clinical IV infusion/injection.  
The radiation exposure associated with this study is comparable to the dose for other widely used 
clinical nuclear medicine procedures. 
Subjects will be monitored for adverse events during each [18F]FLT imaging session.  Adverse 
events are defined as any signs of illness or symptoms that have appeared or worsened since the 
infusion of [18F]FLT.  At the beginning and end of the [18F]FLT imaging session, subjects will be 
questioned regarding any appearance or change in signs and symptoms. The adverse events to be 
specifically monitored during the infusion include localized discomfort at the IV injection site, 
pain, respiratory difficulties, flushing, dizziness, itching/rash, and any other symptoms that could 
be secondary to an anaphylactic reaction.
10.4.2 STUDY SPECIFIC RISKS/ADVERSE EVENT REPORTING
Qualifying Adverse Events (AEs), including Serious Adverse Events (SAEs), as defined herein, 
will be reported via the Adverse Event Expedited Reporting System (AdEERS) application.  All 
Adverse Events, as defined herein, will, in addition, be reported via CDUS Complete, C3D, or 
other AE reporting system as specified below. 
AdEERS is an electronic, internet based expedited Adverse Event reporting system operated by 
NCI/CTEP.  It is generally used to capture and disseminate information on relatively significant 
Adverse Events, based upon trial stage, expectedness, severity, and attribution.  However, it may 
be used to report adverse events of all types if AdEERS reporting is required per protocol.  

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For this study, Adverse Event reporting must follow the guidelines and timing requirements 
below.  The latest version of the NCI/CTEP Adverse Event Reporting Requirements document, 
which is available at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/newadverse_2006
.pdf
provides additional details, and may be consulted as a reference, but does not supersede AE 
reporting as specified in this protocol. 
The electronic-AdEERS AE system is to be used for all ‘expedited reporting’ events as defined 
herein.  
10.4.3 General Definitions
10.4.3.1 Adverse Event (AE)  
For the purpose of this study, an Adverse Event is an untoward medical condition experienced by 
a study participant during the Adverse Event reporting period defined in Table 9 of the 
protocol, or by applicable guidance, regulation, or policy.  An AE is any unfavorable or 
unintended sign (including an abnormal laboratory finding), symptom or disease temporally 
associated with participation in the study, regardless of exposure to an agent or procedure, 
and regardless of whether it is considered to be caused by the agent, device, or process 
under investigation. 
If there is thought to be a conflict between the protocol and a regulatory or guidance source, 
consult the CIP Clinical Trials Branch.  If a decision must be made pending final clarification, 
the stricter requirement should be applied.
10.4.3.2 Life-Threatening Adverse Event  
A life-threatening AE is any adverse event that places the study participant, in the clinical 
opinion of the investigator, at immediate risk of death.
10.4.3.3 Serious Adverse Event (SAE)  
An SAE is defined as any untoward medical occurrence that meets any one of the following 
criteria:
x
Results in death or is life-threatening at the time of the event
x
Requires inpatient hospitalization, or prolongs a hospitalization
x
Results in a persistent or significant disability/incapacity
x
Is a congenital anomaly/birth defect (in a participants offspring)
NOTE: Any event that:
x Follows IND agent administration, AND
x Occurs within the Expedited AE reporting period defined in the Reporting Table [See 
Table 9 Below], AND
x Meets the definition of a Serious Adverse Event (SAE), as described above
MUST be reported through the AdEERS system.

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All SAEs are to be followed by the investigator until resolution, stabilization, scientifically 
and clinically satisfactory explanation as to attribution and etiology, or until subject is lost to 
follow up. 
10.4.3.4 Adverse Event Expedited Reporting System (AdEERS)  
AdEERS is a web-based system created by NCI for electronic submission of expedited AE 
reports & is to be used in this study.  
10.4.3.5 Investigational Agent  
An investigational agent is any agent held under an Investigational New Drug (IND) application.  
For purposes of this study 3'-deoxy-3'-18F fluorothymidine (FLT) is an investigational agent.
10.4.3.6 Clinical Data Update System (CDUS/Complete CDUS)
CDUS/Complete CDUS is a data collection system used to capture clinical data.  Complete 
CDUS is capable of capturing Adverse Event Data and is not being used in this study. 
10.4.3.7 C3D
C3D is an integrated clinical trial data collection and AE reporting system for reporting of ALL 
Adverse Events, including those also requiring expedited reporting via (e)-AdEERS.  Trials that 
will use C3D have been developed using C3D to create customized eCRFs.  
This trial will use C3D.  [See CDUS above.]
10.4.3.8 Protocol Deviation (NIH Definition)
Any change, divergence, or departure from the IRB approved study procedures in a research 
protocol that does not have a major impact on the subject’s rights, safety or well-being, or the 
completeness, accuracy and reliability of the study data.
10.4.3.9 Protocol Violation (NIH Definition)
Any change, divergence, or departure from the IRB-approved study procedures in a research 
protocol that does have a major impact on the subject’s rights, safety, or well-being and/or the 
completeness, accuracy and reliability of the study data.
10.4.3.10
Unanticipated Problem
Any incident, experience, or outcome that:
x
Is unexpected in terms of nature, severity, or frequency in relation to 
(a) the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents, and
(b) the characteristics of the subject population being studied; AND
x
Is related or possibly related to participation in the research; AND
x
Places subjects or others at a greater risk of harm (including physical, psychological, 
economic, or social harm) than was previously known or recognized.
10.4.4 AE Reporting Requirements 
The Investigator’s Brochure has been consulted in compiling the Adverse Events list in this 
protocol and the Informed Consent for the study.  
NOTE: 24-Hour Notification for CIP IND Trials

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The adverse event 24-hour notification requirement provides an early detection system for 
potential safety problems. Adverse events that must be reported within 24-hours of learning of 
the event are dependent upon the phase of trial, the agent/intervention (investigational or 
commercial), whether the event is expected or unexpected, the grade, and attribution. Table 9
and footnotes to the table outline 24-hour notification requirements for AEs in trials utilizing an 
agent under a CIP IND.  Adverse events that fulfill the 24-hour reporting requirement must be 
reported electronically via AdEERS.  To ensure vigilance for AEs that require 24-hour 
notification, AdEERS is programmed to facilitate complete, timely submission. 
10.4.5 Comprehensive Adverse Events & Potential Risks Lists (CAEPR) for 3'-deoxy-3'-
[F-18]fluorothymidine (NSC 743144)
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the Agent 
Specific Adverse Event List (ASAEL), appears in a separate column and is identified with bold 
and italicized text. This subset of AEs (ASAEL) contains events that are considered 'expected' 
for expedited reporting purposes only. Refer to the 'CTEP, NCI Guidelines: Adverse Event 
Reporting Requirements' 
http://ctep.info.nih.gov/protocolDevelopment/default.htm#adverse_events_adeers for further 
clarification. The CAEPR does not provide frequency data; refer to the Investigator's Brochure 
for this information. Below is the CAEPR for 3'-deoxy-3'-[F-18]fluorothymidine.
Version 1.0, July 1, 2010 1
Category
(Body 
System)
Adverse Events2 with Possible
Relationship to 3'-deoxy-3'-[F-
18]fluorothymidine
(CTCAE v4.0 Term)
EXPECTED AEs FOR ADEERS REPORTING 
Agent Specific Adverse Event List
(ASAEL)
No AEs reported in human studies2,3.
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be 
distributed to all Principal Investigators at the time of revision.  The current version can be 
obtained by contacting PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, 
the protocol, and the agent should be included in the e-mail.
2No adverse events have been attributed to Positron-Emission Tomography (PET) 
imaging/diagnostic administration of [3'-deoxy-3'-[F-18]fluorothymidine at the levels described 
in the Investigators Brochure.  Therefore, no adverse events are expected as a result of the 
intravenous (IV) administration of 3'-deoxy-3'-[F-18]fluorothymidine for typical PET imaging 
applications.  
3As with many intravenously administered agents, 3'-deoxy-3'-[F-18]fluorothymidine could 
cause an allergic reaction that could potentially pose a threat to life (anaphylaxis).  This has not 
been observed in limited human exposure to date.  Reasonable precautions should be taken, 
consistent with normal radiologic and clinical facility practice.  The patient should be monitored 

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until the PET procedure is completed, and trained personnel and emergency equipment should be 
available per facility standards.
10.4.6 Adverse Event Characteristics 
Expected Adverse Event:  An expected AE is an event that is listed in the protocol or the 
Investigator’s Brochure.
Unexpected Adverse Event: An unexpected AE is an event that is NOT listed in the protocol 
or the Investigator’s Brochure.
Attribution:  Attribution is a clinical determination, by the investigator, as to whether an AE is 
related to a medical treatment or procedure.  Attribution categories are:
x
Definite:     The AE is clearly related to a treatment or procedure
x
Probable:   The AE is likely related to a treatment or procedure
x
Possible:     The AE may be related to a treatment or procedure
x
Unlikely:    The AE is likely unrelated to a treatment or procedure
x
Unrelated:  The AE is clearly not related to a treatment or procedure
NOTE:  Attribution is part of the assessment of an adverse event.  Determining that 
an event is ‘unlikely related’ or ‘unrelated’ to a study agent or procedure does NOT 
make the event unreportable, or disqualify the event as an AE.  As defined above, an 
AE is reportable as specified herein if it occurred:
“during the Adverse Event reporting period defined in Table 9 of the protocol, or by 
applicable guidance, regulation, or policy.”
Grade:  Grade denotes the severity of the AE.  An AE is graded using the following categories:
x
Mild
x
Moderate
x
Severe
x
Life-threatening or disabling
x
Fatal
10.4.7 CTCAE term (AE description and grade)
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 3.0 will be utilized until December 31, 2010 for AE reporting.  
CTCAE version 4.0 will be utilized beginning January 1, 2011. All appropriate clinical areas 
should have access to a copy of the CTCAE version 4.0.  A copy of the CTCAE can be 
downloaded from the CTEP web site (http://ctep.cancer.gov).
10.4.8 Expectedness
AEs can be ‘Unexpected’ or ‘Expected’ for expedited reporting purposes only.  ‘Expected’ AEs, 
obtained from the Investigators Brochure, are as follows:  allergic reaction/anaphylaxis, which 
appears to be highly unlikely, and risks that would be associated with any clinical IV 
infusion/injection.

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10.4.9 Expedited Adverse Event Reporting
Expedited AE reporting for this study must use electronic AdEERS (Adverse Event Expedited 
Reporting System), accessed via the CTEP home page (http://ctep.cancer.gov).  Site personnel will 
be trained in required AE identification and reporting procedures.  These requirements are briefly 
outlined in Table 9 below.
In the rare event when Internet connectivity is disrupted a 24-hour notification is to be made to 
NCI by telephone at: 301-897-7497, or 301-897-7402 for CIP studies. An electronic report
MUST be submitted immediately upon re-establishment of internet connection. Please note that 
all paper AdEERS forms have been removed from the CTEP website and will NO LONGER be 
accepted.
10.4.10 Expedited Reporting Guidelines
Table 9 Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for 
Adverse Events that Occur on Studies under an IND/IDE within 30 Days of the Last 
Administration of the Investigational Agent/Intervention 1, 2
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not they are 
considered related to the investigational agent(s)/intervention (21 CFR 312.64)
An adverse event is considered serious if it results in ANY of the following outcomes:  
1)
Death
2)
A life-threatening adverse event 
3)
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4)
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 
5)
A congenital anomaly/birth defect. 
6)
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be 
considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH 
E2A and ICH E6).
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via AdEERS within the 
timeframes detailed in the table below.
Hospitalization
Grade 1 and Grade 2 Timeframes
Grade 3-5
Timeframes
Resulting in 
Hospitalization 
KUV
10 Calendar Days
24-Hour 5 Calendar Days
Not resulting in 
Hospitalization 
KUV
Not required
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific Protocol 
Exceptions to Expedited Reporting (SPEER) portion of the CAEPR.
Expedited AE reporting timelines are defined as:
o
“24-Hour; 5 Calendar Days” - The AE must initially be reported via AdEERS within 24 hours of learning of the AE, 
followed by a complete expedited report within 5 calendar days of the initial 24-hour report.
o
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of learning 
of the AE.
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention and have 
an attribution of possible, probable, or definite require reporting as follows: 
Expedited 24-hour notification followed by complete report within 5 calendar days for:

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x
All Grade 3, 4, and Grade 5 AEs
Expedited 10 calendar day reports for:
x
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, rounded UP to the 
nearest whole day, after the agent/intervention was last administered.  Footnote “1” above applies after this reporting period.
Effective Date:  May 5, 2011
10.4.11 Routine Adverse Event Reporting
All Adverse Events must be reported in routine C3D study data submissions.  AEs reported through 
AdEERS must also be reported in routine study data submissions.
10.5 NCI-IRB Reporting
10.5.1 NCI-IRB Expedited Reporting of Adverse Events, Unanticipated Problems, and 
Deaths
The Protocol PI will report to the NCI-IRB:
x
All unexpected serious adverse events that are possibly, probably, or definitely related to 
the research 
x
All deaths, except deaths due to progressive disease 
x
All Protocol Violations or Deviations
x
All Unanticipated Problems
Reports must be received by the NCI-IRB within 7 working days of PI awareness via iRIS.
10.5.2 NCI-IRB Requirements for PI Reporting of Adverse Events at Continuing Review
The protocol PI will report to the NCI-IRB: 
1.
All Grade 2 unexpected events that are possibly, probably or definitely related to 
the research; 
2.
All Grade 3 and 4 events that are possibly, probably or definitely related to the 
research; 
3.
All Grade 5 events regardless of attribution; 
4.
All Serious Events regardless of attribution. 
NOTE: Grade 1 events are not required to be reported.
10.5.3 NCI-IRB Reporting of IND Safety Reports
Only IND Safety Reports that require a sponsor recommended change to the protocol or the 
consent form or in the opinion of the PI increases risks to study participants will need to be 
reported to the NCI IRB.
10.6 NCI Guidance for Reporting Expedited Adverse Events for Multi-Center Trials
The reporting requirements for adverse events in multi-center trials when the NCI PI is 
responsible for the research and the coordination of the other research sites is the same as with 
any NCI intramural research protocol. The site PI must immediately report to the coordinating 
center PI any serious adverse event, whether or not considered drug related, including those 
listed in the protocol or investigator brochure and must include an assessment of whether there is 
a reasonable possibility that the drug caused the event within 48 hours of PI awareness of the 

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event.  The Site PI must also report any protocol deviations or violations to the coordinating 
center PI within 7 days of PI awareness. Participating centers must also submit the report to their 
IRB in accordance with their institutional policies.
11 Pharmaceutical information
11.1 [18F]FLT (IND # 71,260)
Product Description 
11.1.1 How Supplied
Unit dose
11.1.2 Route of Administration
[18F]FLT will be administered by intravenous injection.   
11.1.3 Method of Administration
[18F]FLT is administered by intravenous injection over 10-15 seconds with a saline flush. 
Appropriate shielding to meet the Radiation Safety Guidelines will be used. 
11.1.4 Availability
[18F]FLT will be synthesized by IBA or Cardinal Heath Pharmacies.
11.1.5 Agent Ordering
See APPENDIX A:  CTEP MULTICENTER GUIDELINES

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[18F]FLT PET for diagnosis and staging of thoracic tumours. Eur J Nucl Med Mol Imaging. 
2003;30(10):1407-12.
77.
Cobben DC, Jager PL, Elsinga PH, Maas B, Suurmeijer AJ, Hoekstra HJ. 3'-18F-fluoro-
3'-deoxy-L-thymidine: a new tracer for staging metastatic melanoma? J Nucl Med. 
2003;44(12):1927-32.
78.
Buck AK, Halter G, Schirrmeister H, Kotzerke J, Wurziger I, Glatting G, et al. Imaging 
proliferation in lung tumors with PET: 18F-FLT versus 18F-FDG. J Nucl Med. 2003;44(9):1426-
31.
79.
Buck AK, Schirrmeister H, Hetzel M, Von Der Heide M, Halter G, Glatting G, et al. 3-
deoxy-3-[(18)F]fluorothymidine-positron emission tomography for noninvasive assessment of 
proliferation in pulmonary nodules. Cancer Res. 2002;62(12):3331-4.
80.
Vesselle H, Grierson J, Muzi M, Pugsley JM, Schmidt RA, Rabinowitz P, et al. In vivo 
validation of 3'deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) as a proliferation imaging tracer in 
humans: correlation of [(18)F]FLT uptake by positron emission tomography with Ki-67
immunohistochemistry and flow cytometry in human lung tumors. Clin Cancer Res. 
2002;8(11):3315-23.
81.
Juweid ME, Stroobants S, Hoekstra OS, Mottaghy FM, Dietlein M, Guermazi A, et al. 
Use of positron emission tomography for response assessment of lymphoma: Consensus of the 
Imaging Subcommittee of International Harmonization Project in lymphoma. J Clin Oncol. 
2007;25(5):571-8.
82.
Shields AF, Briston DA, Chandupatla S, Douglas KA, Lawhorn-Crews J, Collins JM, et 
al. A simplified analysis of [F-18]3'-deoxy-3 '-fluorothymidine metabolism and retention. Eur J 
Nucl Med Mol Imaging. 2005;32(11):1269-75.
83.
Muzi M, Spence AM, O'Sullivan F, Mankoff DA, Wells JM, Grierson JR, et al. Kinetic 
analysis of 3'-deoxy-3'-F-18-fluorothymidine in patients with gliomas. J Nucl Med. 
2006;47(10):1612-21.
84.
Fenstermacher JD BR, and Patlak CS. Methods for quantifying the transport of drugs 
across brain barrier systems. Pharmac Ther. 1981;14:217-48.

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85.
Patlak CS, Blasberg RG. Graphical evaluation of blood-to-brain transfer constants from 
multiple-time uptake data. Generalizations. Journal of Cerbral Blood Flow and Metabolism. 
1985;5:584-90.
86.
Patlak C, Blasberg R, Fenstermacher J. Graphical evaluation of blood-to-brain transfer 
constants from multiple-time uptake data. J Cereb Blood Flow Metab. 1983;3:1-7.
87.
Freedman NM, Sundaram SK, Kurdziel K, Carrasquillo JA, Whatley M, Carson JM, et 
al. Comparison of SUV and Patlak slope for monitoring of cancer therapy using serial PET 
scans. Eur J Nucl Med Mol Imaging. 2003;30(1):46-53.
88.
Hoekstra CJ, Hoekstra OS, Lammertsma AA. On the use of image-derived input 
functions in oncological fluorine-18 fluorodeoxyglucose positron emission tomography studies 
(vol 26, pg 1489, 1999). Eur J Nucl Med. 2000;27(2):214-.
89.
Ohtake T, Kosaka N, Watanabe T, Yokoyama I, Moritan T, Masuo M, et al. Noninvasive 
Method to Obtain Input Function For Measuring Tissue Glucose-Utilization of Thoracic and 
Abdominal Organs. J Nucl Med. 1991;32(7):1432-8.
90.
Hoekstra CJ, Hoekstra OS, Lammertsma AA. On the use of image derived input 
functions in FDG PET studies. J Nucl Med. 1999;40(5):115P-P.
91.
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised 
response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579-86.
92.
Wilson W, Zelenetz A, Niedzwiecki D, Hurd D, Martin S, Czuczman M, et al. MULTI-
CENTER STUDY OF DOSE-ADJUSTED EPOCH-R IN UNTREATED DIFFUSE LARGE B-
CELL LYMPHOMA-CALGB50103 In: communication p, editor. 2008.
93.
Rigacci L, Castagnoli A, Dini C, Carpaneto A, Matteini M, Alterini R, et al. (18)FDG-
positron emission tomography in post treatment evaluation of residual mass in Hodgkin's 
lymphoma: Long-term results. Oncol Rep. 2005;14(5):1209-14.

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13 APPENDIX A:  CTEP MULTICENTER GUIDELINES
13.1 Responsibility of the Protocol Chair 
x
The Protocol Chair will be the single liaison with the CTEP Protocol and Information 
Office (PIO).  The Protocol Chair is responsible for the coordination, development, 
submission, and approval of the protocol as well as its subsequent amendments.  The 
protocol must not be rewritten or modified by anyone other than the Protocol Chair.  
There will be only one version of the protocol, and each participating institution will use 
that document.  The Protocol Chair is responsible for assuring that all participating 
institutions are using the correct version of the protocol.
x
The Protocol Chair is responsible for the overall conduct of the study at all participating 
institutions and for monitoring its progress.  All reporting requirements to CTEP are the 
responsibility of the Protocol Chair. 
x
The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure 
safety of the patients.
x
The Protocol Chair will be responsible for the review of and timely submission of data 
for study analysis.
13.2 Responsibilities of the Coordinating Center
x
Each participating institution will have an appropriate assurance on file with the Office 
for Human Research Protection (OHRP), NIH. The Coordinating Center is responsible 
for assuring that each participating institution has an OHRP assurance and must maintain 
copies of IRB approvals from each participating site. 
x
Prior to the activation of the protocol at each participating institution, an OHRP form 
310 (documentation of IRB approval) must be submitted to the CTEP PIO.
x
The Coordinating Center is responsible for central patient registration.  The Coordinating 
Center is responsible for assuring that IRB approval has been obtained at each 
participating site prior to the first patient registration from that site.
x
The Coordinating Center is responsible for the preparation of all submitted data for 
review by the Protocol Chair.
x
The Coordinating Center will maintain documentation of AE reports.  There are two 
options for AE reporting: (1) participating institutions may report directly to CTEP with a 
copy to the Coordinating Center, or (2) participating institutions report to the 
Coordinating Center who in turn report to CTEP.  The Coordinating Center will submit 
AE reports to the Protocol Chair for timely review.
x
Audits may be accomplished in one of two ways:  (1) source documents and research 
records for selected patients are brought from participating sites to the Coordinating 
Center for audit, or (2) selected patient records may be audited on-site at participating 
sites.  If the NCI chooses to have an audit at the Coordinating Center, then the 
Coordinating Center is responsible for having all source documents, research records, all 
IRB approval documents, NCI Drug Accountability Record forms, patient registration 
lists, response assessments scans, x-rays, etc. available for the audit.
13.3 Agent Ordering
Investigational agents may be ordered by a participating site only after the initial IRB approval 
for the site has been forwarded by the Coordinating Center to the CTEP PIO.

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The WRNMMC study coordinator or designee will fax a copy of the eligibility checklist, 
consent, and supporting source documentation to the Molecular Imaging Program. All 
investigational agents will be ordered by the Molecular Imaging Program Staff.
Once eligibility is verified and a scan date is arranged, the Molecular Imaging Program Staff will 
order the [18F]FLT from IBA and Cardinal Heath Pharmacies.
Doses of the investigational agent ordered for patients admitted to the NIH CC, [18F]FLT will be 
delivered to the Clinical Center Nuclear Medicine Department. Doses of the investigational 
agent ordered for patients admitted to the WRNMMC, [18F]FLT will be delivered to the 
WRNMMC Nuclear Medicine Department.

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14
Appendix B: Participating Site Expedited Event Report Form
PROTOCOL 
No.
Site investigator (Name, Contact Telephone Number):
NCI IRB Report 
Form
 
 
PROTOCOL TITLE:
PARTICIPATING SITE LOCATION:
Date Site Investigator Notified of Event: Click here to enter a date.
Description of Participant:
Sex: 
Male     
Female
Age: 
Diagnosis: 
Is this an Initial or a Follow-Up Report?    
Initial     
Follow up
For Follow up, AE reference # provided by NIH, if applicable: 
If this is a Follow-up report, describe what was updated from the initial report: 
Category of Report (select all that apply):
Unexpected Serious Adverse Event that is possibly, probably, or definitely related to 
research
Death, except due to progressive disease
Protocol Violation
Protocol Deviation
Unanticipated Problem
If reporting a Serious Adverse Event, please select appropriate outcome category:
Death
Life Threatening
Required or Prolonged Hospitalization
Caused Persistent or Significant Disability/Incapacity
Resulted in Congenital Anomalies or Birth Defects
Required Intervention to Prevent Permanent Impairment or Death

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Did this result in? (select all that apply)
Harm or significant or substantive risk of harm to the research subject 
A compromise in the scientific integrity of the data collected for the study
A breach of human subject protection regulations, policies or procedures 
Non-compliance with human subject protection regulations, policies or procedures
A Protocol Deviation that does not impact the safety or welfare of subjects, or protocol 
integrity
Have similar adverse events occurred on this protocol at this site?  
Yes    
No
Description of similar events:
Brief description of the event/incident being reported:
Is this event “unexpected”? (i.e., not described in protocol, consent, or Investigator Brochure)
YES 
NO If yes, explain:
Does the event suggest the research places subjects or others at a greater risk of harm?
YES 
NO
If yes, explain:
What steps do you plan to take as a result of this report? Select all that apply.
No Action Required
Amend protocol
Amend consent document
Inform current participants and document in the medical record
Terminate protocol
Educate staff
Conduct audit

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Suspend enrollment
Other
Specify other steps taken:
In addition to the NCI IRB, is this report being submitted to the local IRB? 
Yes
No
Adverse Event Information:
CTCAE 
Term
Date of 
Event
Location 
of Event
CTCAE 
Version
CTCAE 
Grade
Attribution 
to 
Research
Attribution 
to IND 
Agent
Expected
Click 
here for 
date.
Location 
of Event
Version 
No
Grade 
No
Attribution
Attribution
Yes/No
Click 
here for 
date.
Location 
of Event
Version 
No
Grade 
No
Attribution
Attribution
Yes/No
Click 
here for 
date.
Location 
of Event
Version 
No
Grade 
No
Attribution
Attribution
Yes/No
Click 
here for 
date.
Location 
of Event
Version 
No
Grade 
No
Attribution
Attribution
Yes/No
Click 
here for 
date.
Location 
of Event
Version 
No
Grade 
No
Attribution
Attribution
Yes/No
Click 
here for 
date.
Location 
of Event
Version 
No
Grade 
No
Attribution
Attribution
Yes/No
Click 
here for 
date.
Location 
of Event
Version 
No
Grade 
No
Attribution
Attribution
Yes/No
Click 
here for 
date.
Location 
of Event
Version 
No
Grade 
No
Attribution
Attribution
Yes/No
Click 
here for 
date.
Location 
of Event
Version 
No
Grade 
No
Attribution
Attribution
Yes/No
Click 
here for 
Location 
of Event
Version 
No
Grade 
No
Attribution
Attribution
Yes/No

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CTCAE 
Term
Date of 
Event
Location 
of Event
CTCAE 
Version
CTCAE 
Grade
Attribution 
to 
Research
Attribution 
to IND 
Agent
Expected
date.
REPORTED BY:
Printed Name:
_______________________________________________________________
Date:
________________________________________________________________

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15 Appendix C: Model Informed Consent Document (Residual Mass)
NIH CC Protocol #: 08C0200
NCI CTEP #: 8333
Local Protocol #: pending_________
A pilot study of 18F fluorothymidine (FLT) PET/CT in lymphoma
*NOTES FOR INFORMED CONSENT AUTHORS:
x
Instructions and examples for informed consent authors are in [italics].
x
A blank line, __________, indicates that the local investigator should provide the 
appropriate information before the document is reviewed with the prospective research 
participant. 
x
The term ‘study doctor’ has been used throughout the template because the Principal 
Investigator of a cancer treatment trial is a physician.   If this template is used for a trial 
where the Principal Investigator is not a physician, another appropriate term should be 
used instead of ‘study doctor’. 
x
The template date in the header is for reference to this template only and should not be 
included in the informed consent form given to the prospective research participant. 
*These notes for authors and investigators are instructional and should not be included in 
the informed consent form given to the prospective research participant.
INTRODUCTION
We invite you to take part in a research study at the (your institution).
First, we want you to know that:
Taking part in (your institution) is entirely voluntary.
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future.
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your (your institution) or research team before you 
agree to the study.
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at (your institution), or 
with family, friends or your personal physician or other health professional.  
Description of Research Study
You have been invited to participate in this study because you have lymphoma. Response to 
treatment in lymphomas may be difficult to assess by conventional PET/CT scans. Conventional 
PET/CT scans are typically done using a sugar-like radioactive tracer called FDG and low dose 
x-rays. In many instances, FDG PET/CT scans can show uptake suggestive of active disease and 
presence of a mass after chemotherapy despite the fact that no live cancer cells are present. 
Doctors have particular problems in evaluating response to treatment when this happens because 

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they can’t tell if this mass is just dead tumor cells or active cancer. We hope that a new PET 
radioactive tracer called 18F- Fluorothymidine (FLT) may help us to better evaluate treatment 
response. This is why we have asked you to participate in this study.
Positron emission tomography (PET) is a type of scan that uses a large donut shaped detection 
device. The scanner contains crystals that pick up tiny radiation signals given off by radioactive 
substances (tracers) that have been injected into the vein. The images generated by the scanner 
show where the radioactive tracer is in the body.  The CT portion of the PET/CT is performed 
with low dose x-rays that go through your body and help us to better localize where the 
radioactive tracer is concentrating.
If your original FDG PET/CT imaging was performed at an outside institution and is not of 
adequate imaging quality, you may be asked to undergo a repeat FDG PET/CT study at NIH.  If 
this is the case, you will undergo the routine 1- hour post injection imaging.
FLT is an experimental tracer which has high uptake in tissues involved in cellular division such 
as tumors. By injecting a small amount intravenously, we can image where FLT accumulates in 
the body.
Numerous small PET studies using FLT have been performed with no adverse effects ever 
reported. The amount of radiation is within the NIH radiation safety guidelines for protection of 
research volunteers. 
By enrolling is this study, you will be asked to perform an additional FLT PET/CT scan at the 
end of your chemotherapy. This is in addition to standard of care FDG PET/CT studies ordered 
by your doctor. 
Patients with a mass that can be seen on FDG PET/CT routinely have a biopsy performed as 
standard of care to determine if there are live tumor cells remaining. 
There may be additional blood tests performed before the FLT PET scan can be scheduled. 
These are to be as certain as we can that the injection of FLT will not cause side effects. These 
tests will be performed to assess your liver function and will require about two teaspoonfuls of 
blood. Women able to have children will have an additional teaspoonful of blood collected in 
order to test for pregnancy. Pregnant women cannot participate in this study due to potential 
negative health effects to the unborn baby.  
On the day of your FLT PET/CT study, you will come to the Nuclear Medicine Department at 
NIH and an intravenous line will be placed in your arm. You will be asked to lie on your back at 
the PET/CT scanner table. The table will then be advanced into the scanner. FLT will be injected 
in the vein over a 10-15 second period. Subsequently, PET/CT imaging over the tumor will be 
performed for 60 minutes, and immediately afterwards, a whole body scan will be performed (an 
additional 25-35 minutes). It is important that you remain still during these scans. 120 minutes 
after the injection, a regional (with your target tumor in the field of view) PET/CT images will be 
performed in a similar fashion for 25-35 minutes. Please note that for the additional sets of 

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images re-injection of tracer is not necessary. Doctors and nurses will be supervising the whole 
procedure and you should ask them any questions you have concerning this study. Additional 
blood samples (two teaspoons) will be collected from your vein at 60 and 120 minutes after the 
FLT injection to determine the amount of FLT that remains in your blood.
Up to 30 subjects will be enrolled in this arm of the trial. Patients will be enrolled at either the 
NIH Clinical Center or the Walter Reed National Military Medical Center.
Alternative Approaches or Treatments
You are not obligated to participate in this study.  If you decide not to participate, it will not alter 
your planned treatment.
Risks or Discomforts of Participation
There are a few possible risks of [F-18]FLT PET and PET/CT scans.  The most common ones 
are not considered serious.  Any serious risks of [F-18]FLT  PET or PET/CT scans are 
considered very unlikely.  All of the known risks are described below.
Possible risks from having an intravenous (IV) injection: 
x
Bruising, pain, or infection at the injection site
x
Leaking of IV fluid into tissues near the injection 
x
Inflammation of the vein at the injection site
x
Allergic reaction, which could be serious or life threatening
x
Dizziness if you stand up quickly
Possible risks from having a PET scan in general:
x
Claustrophobia (feeling anxious and ‘closed in’)
x
Discomfort from lying still on your back for a total of about 95 minutes during the 
scans
Possible risks from radiation exposure:
Each dose of [F-18]FLT will expose you to about [e.g. one-half to three –quarters] of the amount 
of radiation in a routine CT scan of a large body area such as your abdomen.  Because we also 
need to do a CT, along with the [F-18]FLT PET, you could get up to another full CT dose of 
radiation at each scan depending on the scanner used.
Using the standard way of describing radiation dose, from participating in this study, you will 
receive a total of approximately 3.2 rem to your liver, 2.7 rem to your pancreas, your stomach, 
and adrenal glands,2.6 rem to your small and upper large intestines. All other organs will receive 
smaller amounts of radiation.
Although each organ will receive a different dose, the amount of radiation exposure you will 
receive from these procedures is equal to a uniform whole-body exposure of 1.5 rem. This 
calculated value is known as the “effective dose” and is used to relate the dose received by each 

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organ to a single value. The amount of radiation received in this study is within the dose 
guidelines established by the NIH Radiation Safety Committee for research subjects. The 
guidelines is an effective dose of 5 rem (or 5,000 mrem) received per year.
For comparison, the average person in the United States receives a radiation exposure of 0.3 
rem per year from natural background sources, such as from the sun, outer space, and from 
radioactive materials that are found naturally in the Earth’s air and soil. The dose that you will 
receive from this research study is about the same amount you would normally receive in 4.6
years from these natural sources. 
The effects of radiation exposure on humans have been studied for over 60 years. In fact, these 
studies are the most extensive ever done of any potentially harmful agent that could affect 
humans. In all these studies, no harmful effects to have been observed from the levels of 
radiation you will receive by taking part in this research study. However, scientists disagree on 
whether radiation doses at these levels are harmful. Even though no effects have been observed, 
some scientists believe that radiation can be harmful at any dose - even low doses such as those 
received during this research.
If you are pregnant or breastfeeding you will not be permitted to participate in this protocol.
The unborn or nursing children are more sensitive to radiation than children or adults.
If you would like more information about radiation and examples of exposure levels from other 
sources, please ask the investigator for a copy of the pamphlet called, An Introduction to 
Radiation for NIH Research Subjects.
Please tell your doctor if you have taken part in other research studies or received any medical 
care at the NIH or other places/hospitals that used radiation. This way we can make sure that 
you will not receive too much radiation. Consider x-rays taken in radiology departments, 
cardiac catheterization, and fluoroscopy as well as nuclear medicine scans in which radioactive 
materials were injected into your body.
Experimental FLT PET imaging may reveal new information that would result in further studies 
(e.g., biopsies) and interventions that might not be necessary. The decision to act on findings on 
the experimental FLT PET study will be made by you and your referring physician.
It is possible that you may experience some side effects that we cannot anticipate. For that 
reason, you will be watched closely so that we can treat any side effects early. 
Potential Benefits of Participation
As this is NOT a treatment protocol, you are not likely to have any direct benefits.
Alternative Treatments:
You should discuss your condition and prognosis with other doctors. Ask your doctor any 
questions you have and the choices that are available to you. Possible options are to proceed with 
the embolization procedure without participating in the study or not to have the embolization 

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procedure at all. Alternatives to the standard procedure will be explained elsewhere and are not 
related to this particular study.
Can I stop being in the study?
Yes.  You can stop taking part in the study at any time. However, if you decide to stop taking 
part in the study, we would like you to talk to the study doctor and your regular doctor first.
It is important to tell the study doctor if you are thinking about stopping so any risks from the
intervention can be evaluated by your doctor.  Another reason to tell your doctor that you are 
thinking about stopping is to discuss what follow-up care and testing could be most helpful for 
you.
The study doctor may stop you from taking part in this study at any time if he/she believes it is in 
your best interest; if you do not follow the study rules; or if the study is stopped.
What are the costs of taking part in this study? 
(If applicable, inform the patient of any tests or procedures for which there is no charge. 
Indicate if the patient and/or health plan is likely to be billed for any charges associated with 
these ‘free’ tests or procedures.) 
You will not be paid for taking part in this study.
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage .  You 
can print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site.
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy.
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Organizations that may look at 
and/or copy your medical records for research, quality assurance, and data analysis include:
x
[List 
relevant 
organizations 
like 
study 
sponsor(s), 
pharmaceutical 
company 
collaborators, local IRB, etc.] 
x
The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people.
x
National Cancer Institute Institutional Review Board
A description of this clinical trial will be available on http://www.Clinicaltrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most the 
Web site will include a summary of the results.  You can search this Web site at any time. 
[Note to Informed Consent Authors: the above paragraph complies with the new FDA regulation 
found at 21 CFR 50.25(c) and must be included verbatim in all informed consent documents. The 
text in this paragraph cannot be revised.]
[Note to Local Investigators: The NCI has recommended that HIPAA regulations be addressed 
by the local institution.  The regulations may or may not be included in the informed consent 
form depending on local institutional policy.]
What happens if I am injured because I took part in this study?

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It is important that you tell your study doctor, __________________ [investigator’s name(s)], if 
you feel that you have been injured because of taking part in this study.  You can tell the doctor 
in person or call him/her at __________________ [telephone number].
You will get medical treatment if you are injured as a result of taking part in this study.  You 
and/or your health plan will be charged for this treatment.   The study will not pay for medical 
treatment.  
What are my rights if I take part in this study?
Taking part in this study is your choice.  You may choose either to take part or not to take part in 
the study.  If you decide to take part in this study, you may leave the study at any time.   No 
matter what decision you make, there will be no penalty to you and you will not lose any of your 
regular benefits.  Leaving the study will not affect your medical care.  You can still get your 
medical care from our institution.   
We will tell you about new information or changes in the study that may affect your health or 
your willingness to continue in the study.
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form.  
Who can answer my questions about the study?
You can talk to your study doctor about any questions or concerns you have about this study.  
Contact your study doctor __________________ [name(s)] at __________________ [telephone 
number].
Where can I get more information?
You may call the National Cancer Institute's Cancer Information Service at: 
1-800-4-CANCER (1-800-422-6237) 
You may also visit the NCI Web site at http://cancer.gov/
x
For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/
x
For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/
You will get a copy of this form.  If you want more information about this study, ask your study 
doctor.

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16 Appendix D: Model Informed Consent Document (Early Response)
NIH CC Protocol #: 08C0200
NCI CTEP #: 8333
Local Protocol #: pending________
A pilot study of 18F fluorothymidine (FLT) PET/CT in lymphoma
*NOTES FOR INFORMED CONSENT AUTHORS:
x
Instructions and examples for informed consent authors are in [italics].
x
A blank line, __________, indicates that the local investigator should provide the 
appropriate information before the document is reviewed with the prospective research 
participant. 
x
The term ‘study doctor’ has been used throughout the template because the Principal 
Investigator of a cancer treatment trial is a physician.   If this template is used for a trial 
where the Principal Investigator is not a physician, another appropriate term should be 
used instead of ‘study doctor’. 
x
The template date in the header is for reference to this template only and should not be 
included in the informed consent form given to the prospective research participant. 
*These notes for authors and investigators are instructional and should not be included in 
the informed consent form given to the prospective research participant.
INTRODUCTION
We invite you to take part in a research study at the (your institution).
First, we want you to know that:
Taking part in (your institution) is entirely voluntary.
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future.
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your (your institution) or research team before you 
agree to the study.
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at (your institution), or 
with family, friends or your personal physician or other health professional.  
Description of Research Study
You have been invited to participate in this study because you have lymphoma. As standard of 
care, your doctor will obtain conventional PET/CT scans to evaluate your response to 
chemotherapy. Conventional PET/CT scans are typically done using a sugar-like radioactive 
tracer called FDG and low dose x-rays. They are usually performed before treatment and after 

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the completion chemotherapy.  Even though, FDG PET/CT is valuable in monitoring treatment 
response, we hope that a new PET radioactive tracer called 18F- fluorothymidine (FLT) PET/CT 
will be better able predict final response to treatment. We, the study team, will work with your 
clinical provider to see if this early imaging helped predict your response to therapy. This is why 
we have asked you to participate in this study.
Positron emission tomography/computed tomography (PET/CT) is a type of scan that uses a 
large donut shaped detection device. The scanner contains crystals that pick up tiny radiation 
signals given off by radioactive substances (tracers) that have been injected into the vein. The 
images generated by the scanner show where the radioactive tracer is in the body.  The CT 
portion of the PET/CT is performed with low dose x-rays that go through your body and help us 
to better localize where the radioactive tracer is concentrating.
FLT is an experimental tracer which has high uptake in tissues involved in cellular division such 
as tumors. By injecting a small amount intravenously, we can image where FLT accumulates in 
the body.
Numerous small PET studies using FLT have been performed with no adverse effects ever 
reported. 
By enrolling is this study, you will be asked to undergo an FLT PET/CT scan: before beginning 
therapy, after 2 cycles of therapy and following completion of your chemotherapy. It is generally 
standard of care to undergo FDG PET/CT imaging prior to beginning treatment and at the 
completion of therapy.  Some small studies have suggested that FDG PET/CT performed during 
therapy may be predictive of outcome. For this study, we are asking you to undergo an additional 
mid-therapy FDG PET/CT study, which will be compared with the mid treatment FLT PET/CT. 
You will also be giving us permission to collect follow-up information regarding your progress 
for up to three years after treatment. 
There may be additional blood tests performed before the FLT PET scan can be scheduled. 
These are to be as certain as we can that the injection of FLT will not cause side effects. These 
tests will be performed to assess your liver function and will require about two teaspoonfuls of 
blood. Women able to have children will have an additional teaspoonful of blood collected in 
order to test for pregnancy. Pregnant women cannot participate in this study due to potential 
negative health effects to the unborn baby.  
On each day of your FLT PET/CT studies, you will come to the Nuclear Medicine Department at 
(your institution) and an intravenous line will be placed in your arm. You will be asked to lie on 
your back at the PET/CT scanner table. The table will then be advanced into the scanner. FLT 
will be injected in the vein over a 10-15 second period. Subsequently, PET/CT imaging over the
tumor will be performed for 60 minutes, and immediately afterwards, a whole body scan will be 
performed (an additional 25-35 minutes). It is important that you remain still during these scans. 
120 minutes after the injection, another regional (with your target tumor in the field of view) 
PET/CT images will be performed in a similar fashion for 10 minutes. Please note that for the 
additional sets of images re-injection of tracer is not necessary. Doctors and nurses will be 
supervising the whole procedure and you should ask them any questions you have concerning 

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this study. Additional blood samples (two teaspoons) will be collected from your vein at 60 and 
120 minutes after the FLT injection to determine the amount of FLT that remains in your blood.
For the mid-therapy FDG study, you will also come to the Nuclear Medicine Department at 
(your institution) and an intravenous line will be placed in your arm. You will be asked to lie on 
your back at the PET/CT scanner table. The table will then be advanced into the scanner. FDG 
will be injected in the vein over a 10-15 second period. One hour after injection a whole body 
PET/CT will be performed (lasting ~25-35 minutes).
Up to 40 subjects will be enrolled in this arm of the trial. Patients will be enrolled at either the 
NIH Clinical Center or the Walter Reed National Military Medical Center.
Alternative Approaches or Treatments
You are not obligated to participate in this study.  If you decide not to participate, it will not 
alter your planned treatment.
Risks or Discomforts of Participation
There are a few possible risks of [F-18]FLT PET and PET/CT scans.  The most common ones 
are not considered serious.  Any serious risks of [F-18]FLT PET or PET/CT scans are considered 
very unlikely.  All of the known risks are described below.
Possible risks from having an intravenous (IV) injection: 
x
Bruising, pain, or infection at the injection site
x
Leaking of IV fluid into tissues near the injection 
x
Inflammation of the vein at the injection site
x
Allergic reaction, which could be serious or life threatening
x
Dizziness if you stand up quickly
Possible risks from having a PET scan in general:
x
Claustrophobia (feeling anxious and ‘closed in’)
x
Discomfort from lying still on your back for a total of about 95 minutes during the 
scans
Possible risks from radiation exposure:
Each dose of [F-18]FLT will expose you to about [e.g. one-half to three –quarters] of the 
amount of radiation in a routine CT scan of a large body area such as your abdomen.  Because 
we also need to do a CT, along with the [F-18]FLT PET, you could get up to another full CT 
dose of radiation at each scan depending on the scanner used.
A total of 3 FLT PET/CT scans will be performed. 
Using the standard way of describing radiation dose, from participating in this study and 
undergoing all 3 FLT PET/CT scans, you will receive approximately 9.7 rem to your liver, 8.2

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rem to your stomach, and your adrenals, 8.1 rem to your pancreas, and 7.9 rem to your small 
intestines. All other organs will receive smaller amounts of radiation.
Although each organ will receive a different dose, the amount of radiation exposure you will 
receive from these procedures is equal to a uniform whole-body exposure of 4.2 rem. This 
calculated value is known as the “effective dose” and is used to relate the dose received by each 
organ to a single value. The amount of radiation received in this study is within the dose 
guidelines established by the NIH Radiation Safety Committee for research subjects. The 
guidelines is an effective dose of 5 rem (or 5,000 mrem) received per year.
For comparison, the average person in the United States receives a radiation exposure of 0.3 
rem per year from natural background sources, such as from the sun, outer space, and from 
radioactive materials that are found naturally in the earth’s air and soil. The dose that you will 
receive from this research study is about the same amount you would normally receive in 13.7 
years from these natural sources. 
The effects of radiation exposure on humans have been studied for over 60 years. In fact, these 
studies are the most extensive ever done of any potentially harmful agent that could affect 
humans. In all these studies, no harmful effects were ever observed from the levels of radiation 
you will receive by taking part in this research study. However, scientists disagree on whether 
radiation doses at these levels are harmful. Even though no effects have been observed, some 
scientists believe that radiation can be harmful at any dose - even low doses such as those 
received during this research.
If you would like more information about radiation and examples of exposure levels from other 
sources, please ask the investigator for a copy of the pamphlet called, An Introduction to 
Radiation for NIH Research Subjects. Please tell your doctor if you have taken part in other 
research studies or received any medical care at the NIH or other places/hospitals that used 
radiation. This way we can make sure that you will not receive too much radiation. Consider x-
rays taken in radiology departments, cardiac catheterization, and fluoroscopy as well as nuclear 
medicine scans in which radioactive materials were injected into your body.
Experimental FLT PET imaging may reveal new information that would result in further studies 
(e.g., biopsies) and interventions that might not be necessary. The decision to act on findings on 
the experimental FLT PET study will be made by you and your referring physician.
It is possible that you may experience some side effects that we cannot anticipate. For that 
reason, you will be watched closely so that we can treat any side effects early. 
Alternative Treatments:
You should discuss your condition and prognosis with other doctors. Ask your doctor any 
questions you have and the choices that are available to you. Possible options are to proceed 
with the embolization procedure without participating in the study or not to have the 
embolization procedure at all. Alternatives to the standard procedure will be explained 
elsewhere and are not related to this particular study.

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Can I stop being in the study?
Yes.  You can stop taking part in the study at any time. However, if you decide to stop taking 
part in the study, we would like you to talk to the study doctor and your regular doctor first.
It is important to tell the study doctor if you are thinking about stopping so any risks from the
intervention can be evaluated by your doctor.  Another reason to tell your doctor that you are 
thinking about stopping is to discuss what follow-up care and testing could be most helpful for 
you.
The study doctor may stop you from taking part in this study at any time if he/she believes it is in 
your best interest; if you do not follow the study rules; or if the study is stopped.
What are the costs of taking part in this study? 
(If applicable, inform the patient of any tests or procedures for which there is no charge. 
Indicate if the patient and/or health plan is likely to be billed for any charges associated with 
these ‘free’ tests or procedures.) 
You will not be paid for taking part in this study.
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage .  You 
can print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site.
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy.
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Organizations that may look at 
and/or copy your medical records for research, quality assurance, and data analysis include:
x
[List 
relevant 
organizations 
like 
study 
sponsor(s), 
pharmaceutical 
company 
collaborators, local IRB, etc.] 
x
The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people.
x
National Cancer Institute Institutional Review Board
x
A description of this clinical trial will be available on http://www.Clinicaltrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most the
Web site will include a summary of the results.  You can search this Web site at any time. 
[Note to Informed Consent Authors: the above paragraph complies with the new FDA regulation 
found at 21 CFR 50.25(c) and must be included verbatim in all informed consent documents. The 
text in this paragraph cannot be revised.]
[Note to Local Investigators: The NCI has recommended that HIPAA regulations be addressed 
by the local institution.  The regulations may or may not be included in the informed consent 
form depending on local institutional policy.]
What happens if I am injured because I took part in this study?

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It is important that you tell your study doctor, __________________ [investigator’s name(s)], if 
you feel that you have been injured because of taking part in this study.  You can tell the doctor 
in person or call him/her at __________________ [telephone number].
You will get medical treatment if you are injured as a result of taking part in this study.  You 
and/or your health plan will be charged for this treatment.   The study will not pay for medical 
treatment.  
What are my rights if I take part in this study?
Taking part in this study is your choice.  You may choose either to take part or not to take part in 
the study.  If you decide to take part in this study, you may leave the study at any time.   No 
matter what decision you make, there will be no penalty to you and you will not lose any of your 
regular benefits.  Leaving the study will not affect your medical care.  You can still get your 
medical care from our institution.   
We will tell you about new information or changes in the study that may affect your health or 
your willingness to continue in the study.
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form.  
Who can answer my questions about the study?
You can talk to your study doctor about any questions or concerns you have about this study.  
Contact your study doctor __________________ [name(s)] at __________________ [telephone 
number].
Where can I get more information?
You may call the National Cancer Institute's Cancer Information Service at: 
1-800-4-CANCER (1-800-422-6237) 
You may also visit the NCI Web site at http://cancer.gov/
x
For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/
x
For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/
You will get a copy of this form.  If you want more information about this study, ask your study 
doctor.