18-FLT PET/MR Imaging to Predict Graft Failure and Graft Versus Host Disease in Bone Marrow Transplant Patients
Phase: EARLY_PHASE1
Conditions: Graft Vs Host Disease
Sponsor: UNC Lineberger Comprehensive Cancer Center

Study Title: 18-FLT PET/MR Imaging to Predict Graft Failure and Graft Versus Host 
Disease in Bone Marrow Transplant Patients 
 
NCT03546556 
 
Protocol Date: February 7, 2019 
 

LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
LCCC1714 : 18-FLT PET/MR Imaging to Predict Graft Failure and Graft Versus 
Host Disease in Bone Marrow Transplant Patients  
 
Principal Investigator 
Yueh Z. Lee, MD/PhD  
Assistant Professor  
Department of Radiology  
101 Manning Drive, CB# 7510  
Chapel Hill NC, 27599-7510  
919.537-3730 (PHONE)  
919.966.9677 (FAX)  
Email: leey@med.unc.edu 
 
Principal Co-Investigator  
James M. Coghill, MD 
Assistant Professor  
Department of Hematology and Oncology 
101 Manning Drive, CB# 7510  
Chapel Hill NC, 27599-7510  
 
Co-Investigator(s) 
Thomas Shea, MD 
Jonathan Serody, MD 
Paul Armistead, MD/PhD 
Benjamin Vincent, MD 
Marcie Riches, MD 
Katarzyna Jamieson, MD 
William Wood, MD 
Jorge Oldan, MD 
Lauren Burke, MD 
 
Biostatistician  
Allison Deal, MS 
LCCC Biostatistics Core 
Allison_Deal@med.unc.edu 
 
Study Coordinator: 
Soma Prum, MS 
Project Coordinator 
Biomedical Imaging Center (BRIC) 
919-843-9245 (PHONE)  
Email: soma_prum@med.unc.edu 
 
Sponsor: Lineberger Comprehensive Cancer Center 
 
Funding Source: University Cancer Research Fund 

LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
Version Date:  April 5, 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
PROTOCOL AMENDMENT   #4 
 
LCCC1714 : 18-FLT PET/MR Imaging to Predict Graft Failure and Graft Versus 
Host Disease in Bone Marrow Transplant Patients  
 
AMENDMENT INCORPORATES: 
____  Editorial, administrative changes 
_X_   Scientific changes (IRB approval) 
    __    Therapy changes (IRB approval) 
____    Eligibility Changes (IRB approval)   
Summary of Changes –February 7th, 2019 
1. Changing the post transplant window to allow the first scan to occur within +/- 5 days 
instead of +/- 3 days from their day 25 post transplant.  
 
 
 
 
 
 
 
 
THE ATTACHED VERSION DATED 2/7/19 INCORPORATES THE ABOVE 
REVISIONS 
    ATTACH TO THE FRONT OF EVERY COPY OF THIS PROTOCOL 
 
 
 
 
 
 
 
 
 
 
 
 

LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
PROTOCOL AMENDMENT   #3 
 
LCCC1714 : 18-FLT PET/MR Imaging to Predict Graft Failure and Graft Versus 
Host Disease in Bone Marrow Transplant Patients  
 
AMENDMENT INCORPORATES: 
____  Editorial, administrative changes 
____   Scientific changes (IRB approval) 
    __    Therapy changes (IRB approval) 
__X__    Eligibility Changes (IRB approval)   
Summary of Changes – September 4th, 2018 
 
1. Removing the BMI exclusion criteria.  
 
 
 
 
 
 
 
 
 
THE ATTACHED VERSION DATED 9/4/18 INCORPORATES THE ABOVE 
REVISIONS 
    ATTACH TO THE FRONT OF EVERY COPY OF THIS PROTOCOL 
 
 
 
 
 
 
 
 
 

LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
PROTOCOL AMENDMENT   #2 
 
LCCC1714 : 18-FLT PET/MR Imaging to Predict Graft Failure and Graft Versus 
Host Disease in Bone Marrow Transplant Patients  
 
AMENDMENT INCORPORATES: 
_X__  Editorial, administrative changes 
____   Scientific changes (IRB approval) 
    __    Therapy changes (IRB approval) 
____    Eligibility Changes (IRB approval)   
Summary of Changes – June 18th, 2018 
 
1. Grace David added a new coordinator  
2. Removed Rebecca Rainer, who no longer works for BRIC  
 
 
 
 
 
 
 
 
 
 
 
 
THE ATTACHED VERSION DATED 6/18/18 INCORPORATES THE ABOVE 
REVISIONS 
    ATTACH TO THE FRONT OF EVERY COPY OF THIS PROTOCOL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
PROTOCOL AMENDMENT   #1 
 
LCCC1714 : 18-FLT PET/MR Imaging to Predict Graft Failure and Graft Versus 
Host Disease in Bone Marrow Transplant Patients  
 
AMENDMENT INCORPORATES: 
_X__  Editorial, administrative changes 
____   Scientific changes (IRB approval) 
    __    Therapy changes (IRB approval) 
____    Eligibility Changes (IRB approval)   
Summary of Changes – February 8th, 2018 
1. Added Rebecca Rainer as research assistant to the study 
2. Removed Soma Prum, who no longer works for BRIC  
 
 
 
 
 
 
 
 
 
 
 
 
THE ATTACHED VERSION DATED 2/8/18 INCORPORATES THE ABOVE 
REVISIONS 
    ATTACH TO THE FRONT OF EVERY COPY OF THIS PROTOCOL 
 
 
 
 
 
 

LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
LCCC  XXXX: 18-FLT PET/MR Imaging to Predict Graft Failure and Graft 
Versus Host Disease in Bone Marrow Transplant Patients  
 
Principal Investigator 
Yueh Z. Lee, MD/PhD  
Assistant Professor  
Department of Radiology  
101 Manning Drive, CB# 7510  
Chapel Hill NC, 27599-7510  
919.537-3730 (PHONE)  
919.966.9677 (FAX)  
Email: leey@med.unc.edu 
 
 
Principal Co-Investigator  
James M. Coghill, MD 
Assistant Professor  
Department of Hematology and Oncology 
101 Manning Drive, CB# 7510  
Chapel Hill NC, 27599-7510  
 
 
 
 
 
 
Signature Page 
 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable U.S. federal regulations 
and ICH guidelines. 
 
Principal Investigator (PI) Name:_Yueh Lee, MD, PhD______________________ 
 
PI Signature: ___________________ 
 
Date:____________________ 

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PI: Y Lee 
 
UNIVERSITY OF NORTH CAROLINA 
Version Date: April 5,, 2017 
 
 
 
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TABLE OF CONTENTS 
1.0 BACKGROUND AND RATIONALE ....................................................................1 
1.1 Study Synopsis ........................................................................................................1 
1.2 Background ..............................................................................................................1 
1.3 Purpose and Rationale ........................................... Error! Bookmark not defined. 
2.0 STUDY OBJECTIVES AND ENDPOINTS ...........................................................5 
2.1 Primary Objective ....................................................................................................5 
2.2 Secondary Objective ................................................................................................5 
2.3 Primary Endpoint ................................................... Error! Bookmark not defined. 
2.4 Secondary Endpoint ............................................... Error! Bookmark not defined. 
3.0 PATIENT ELIGIBILITY ........................................................................................7 
3.1 Inclusion Criteria .....................................................................................................8 
3.2 Exclusion Criteria ....................................................................................................8 
4.0 STUDY PLAN ...........................................................................................................9 
4.1 Study Duration .........................................................................................................9 
4.2 Schema ....................................................................................................................9 
4.3 Enrollment/Recruitment ........................................................................................10 
4.4 FLT-PET-MRI .......................................................................................................10 
4.5 Medical Records Abstraction ................................................................................10 
4.6 Image Analysis ......................................................................................................11 
4.7 Reader Study ......................................................... Error! Bookmark not defined. 
5.0 EXPECTED RISKS/UNANTICIPATED PROBLEMS .....................................11 
5.1 Expected Risks ......................................................................................................11 

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6.0 TIME AND EVENTS TABLE ...............................................................................12 
6.1 Time and Events Table ..........................................................................................13 
7.0 UNANTICIPATED PROBLEMS .........................................................................13 
7.1 Definition ...............................................................................................................13 
7.2 Reporting ...............................................................................................................15 
7.3 Data and Safety Monitoring Plan ..........................................................................17 
8.0 STATISTICAL CONSIDERATIONS ..................................................................18 
8.1 Study Design .........................................................................................................18 
8.2 Sample Size and Accrual .......................................................................................18 
8.3 Data Analysis Plans ...............................................................................................19 
8.4 Data Management/Audit........................................................................................19 
9.0 STUDY MANAGEMENT ......................................................................................20 
9.1 Institutional Review Board (IRB) Approval and Consent.....................................20 
9.2 Required Documentation .......................................................................................20 
9.3 Registration Procedures .........................................................................................21 
9.4 Adherence to the Protocol .....................................................................................21 
9.5 Amendments to the Protocol .................................................................................22 
9.6 Record Retention ...................................................................................................22 
9.7 Obligations of Investigators...................................................................................23 
10.0 REFERENCES ......................................................................................................24 
11.0 APPENDICES .......................................................................................................26 
Appendix A:  FLT ..........................................................................................................26 
Appendix B: Reader Study Data Collection Form .........................................................29 

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1.0 
BACKGROUND AND RATIONALE 
1.1 
Study Synopsis 
This is a non-randomized, prospective pilot study exploring the use of 
fluorothymidine (FLT)-PET-MRI in the evaluation of allogeneic bone marrow 
transplant patients to potentially predict engraftment success, malignancy relapse, 
and the development of graft versus host. A total of 12 patients who have 
undergone allogeneic bone marrow transplantation will undergo FLT-PET-MRI 
imaging on two separate occasions.  The first scan will occur immediately after 
initial neutrophil count recovery on day +25.  The second scan will occur on 
transplant day +60 by which time stable count recovery should have occurred.  
The findings on the first scan will be correlated with clinical outcomes and 
pathological results on transplant day +35, and the findings on the second scan 
will be correlated with clinical outcomes and pathological results on day +100.  
The day +35 and +100 time points were chosen because allogeneic transplant 
patients at our institution undergo a restaging bone marrow biopsy and aspirate 
with donor/recipient chimerism studies around these days as part of our usual 
standard of care.  In addition to the 12 allogeneic transplant patients, 3 patients 
undergoing autologous stem cell transplant will also be imaged at the same two 
time points in order to determine how much of the FLT signal observed after 
allogeneic transplant is unique to that population and the result of allo-antigen 
driven T cell expansion. 
 
1.1.1  Allogeneic HSCT and Graft-versus-Host Disease 
Allogeneic HSCT is potentially curative for numerous high risk hematologic 
malignancies and offers several advantages over traditional chemotherapy.  First, 
higher doses of cytotoxic chemotherapy and/or irradiation can be given since 
patients are subsequently rescued from the severe myelosuppression induced by 
the pre-transplant conditioning regimen by the infusion of healthy hematopoietic 
stem cells.  Second and perhaps more importantly, mature T cells contained in the 
graft are able to mount immune responses against residual cancer cells surviving 
the conditioning regimen due to major and/or minor MHC disparities between the 
donor and recipient.  Unfortunately, the allo-immune responses driving the GVL 
effect are typically not specific for malignant cells.  As a consequence, donor 
immune cells attack normal host tissues resulting in a process known as acute 
graft-versus-host disease (GVHD).  Acute GVHD is primarily T cell driven, 
usually occurs within the first few months after transplant, and results in skin 
rash, diarrhea, cholestatic liver damage, and, on occasion, acute lung injury.   
 
 
The process by which donor T cells initiate the GVHD process has been extensively 
studied in animal models, and was reviewed previously.1  In brief, naïve, 
“conventional” donor T cells (Tcons) traffic into recipient secondary lymphoid tissue 

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(spleen, lymph nodes, Peyer’s patches) early after transplant, and undergo activation 
and expansion upon exposure to allo-antigens presented by host antigen presenting 
cells.2  Donor T cells then migrate from host secondary lymphoid tissue (SLT) to 
peripheral GVHD “target organs”, where they elicit tissue damage. The efficient 
homing of conventional donor T cells into recipient SLT appears to be absolutely 
required for GVHD pathogenesis in mice as recipient animals lacking all lymphoid 
tissue fail to develop GVHD following allogeneic transplantation.3,4  The relationship 
between donor immune cell expansion within host lymphoid sites and GVHD 
incidence in humans, however, has not been described. 
Allogeneic HSCT patients are at risk for not only GVHD after transplant, but also 
poor stem cell engraftment and/or graft rejection which can ultimately lead to disease 
relapse.  Currently there are no reliable methods for predicting in advance which 
allogeneic transplant patients are destined to develop graft failure/recurrent disease or 
GVHD.  If, however, a radiographic approach could be developed to predict one or 
both of these outcomes, this would be extremely useful clinically.  Both processes are 
modulated by immunosuppressive medications.  Specifically, GVHD is prevented 
and treated with increased immunosuppression and graft failure is treated in the 
opposite manner.  If an imaging modality could prospectively indicate the 
development of either of these processes during their earliest stages, this would allow 
the transplant physician to proactively tailor a patient’s immunosuppression in order 
to hopefully improve transplant outcomes.  Similarly, if an isolated site of disease 
relapse could be identified early, this could lead to directed tissue biopsy and the 
early initiation of pre-emptive chemotherapy and/or radiotherapy. 
 
The current proposal explores the use of a novel imaging modality, FLT PET/MRI, to 
correlate allogeneic transplant outcomes with FLT and MRI findings during early 
stem cell engraftment and at a later time point following stable count recovery.  
Specifically, we will determine if the strength of the early FLT signal within the bone 
marrow correlates with engraftment success and if isolated areas of cellular 
proliferation within the marrow at a later time point might predict for leukemia 
relapse.  In addition, based on the important role that host lymphoid tissues are 
known to play in GVHD pathogenesis in mice, we will determine if the FLT signal 
within host SLT after transplant can predict for the development of GVHD in human 
BMT patients.  Because FLT imaging by itself cannot distinguish between bone 
marrow engraftment/proliferation and the allo-immune driven T cell expansion that 
ultimately results in GVHD, we will image autologous transplant patients as a 
comparator arm.  Autologous HSCT like allogeneic transplantation involves the 
administration of very high doses of chemotherapy to high risk cancer patients in 
order to achieve better tumor kill.  However, in this situation patients are 
administered their own cryopreserved stem cells to reconstitute the ablated 
hematopoietic system.  Under those circumstances there is no allo-immune reactivity 
to drive T cell activation and expansion after transplant, and as a result there is no 
GVHD in the autologous transplant setting.  Thus, these patients will help us to 

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elucidate how much of the FLT signal seen in the allogeneic setting is the result of 
allo-immune driven T cell expansion.  
FLT-Imaging:  Fluorodeoxyglucose (FDG)-PET detects the accumulation of FDG 
in glucose-avid tissue, and is a measure of overall metabolic activity. FDG is 
relatively simple to synthesize, has a long half-life (approximately 2 hours), and 
has a well-understood mechanism of uptake, making it the most commonly used 
radiotracer in oncology.5,6 
  The diagnostic value of FDG-PET, however, is limited by its lack of specificity. 
There has been great interest in taking advantage of the various unique properties 
of tumor cells in PET imaging. Tumor and expanding inflammatory cells show 
increased DNA synthesis during cellular proliferation, making the DNA synthetic 
pathway an attractive target for their visualization.  
FLT, an analogue of the pyrimidine thymidine, has recently become a PET 
imaging agent of interest due to its potential to image cellular proliferation.  
Briefly, FLT is taken up by specific nucleoside transporters on the cell membrane 
via facilitated diffusion, and subsequently phosphorylated by tyrosine kinase 1 
(TK1). Once phosphorylated, FLT is metabolically trapped within the cell. Thus, 
18F labeled FLT detection via PET provides a measure of TK1 activity, which is 
closely linked to the salvage pathway of DNA synthesis and cellular 
proliferation.7   18F-FLT and 18F-FDG PET have the shared advantage of 
utilizing an 18F radiotracer with a 110 minute half-life, making 18F-FLT PET 
feasible in diagnostic PET sites without dedicated on-site cyclotrons. However, 
18F-FLT PET addresses the limitations seen with 18F-FDG PET. Specifically, 
decreased background “noise” is seen with 18F-FLT PET, and confounding 
factors such as muscle uptake do not occur. The invention of PET/MR brings 
together the functional imaging capabilities of PET with the exquisite soft tissue 
discrimination of MR.  
1.1.2 FLT-Imaging in hematologic malignancies 
Previous studies have explored the use of FLT-PET imaging to evaluate bone 
marrow engraftment in both preclinical animal models and human autograft 
patients, and demonstrate the overall feasibility of the imaging approach in the 
HSCT setting.  In work by Awasthi et al. a FLT signal was detectable in the bone 
marrow compartment of Wistar rats within 4 days of syngeneic HSCT, and was 
much more sensitive for early marrow engraftment than traditional FDG-PET 
imaging.8  In work by Woolthuis et al. the authors imaged 16 myeloma or 
lymphoma patients undergoing autologous HSCT transplant following high dose 
chemotherapy and compared them to non-transplanted controls . 9There, the 
investigators observed an enhanced FLT signal in the marrow compartment of 
transplant patients, with a relatively uniform distribution primarily seen in the 
spine and to a lesser extent the pelvis and proximal long bones.   Conversely, in 
work by Agool et al. patients with various active hematologic malignancies 
underwent FLT-PET imaging prior to therapy.10  There, the FLT distribution 

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appeared to be more heterogeneous in appearance, with patchy areas of increased 
tracer uptake noted in patients with multiple myeloma, aplastic anemia, and 
myelodysplastic syndrome.  Collectively, these data suggest that FLT-PET 
imaging is a sensitive tool for evaluating overall marrow recovery after HSCT, 
and that residual FLT activity as well as its overall distribution pattern after 
transplant could be a useful tool for monitoring for early disease relapse.  
Importantly, however, none of these publications evaluated allogeneic transplant 
patients and none correlated FLT-PET imaging results with the subsequent 
development of GVHD, graft failure, or disease relapse.  Furthermore, none have 
attempted to correlate FLT-PET results with simultaneous MRI findings which 
could also be used to predict engraftment success after transplant. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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2.0 
STUDY OBJECTIVES AND ENDPOINTS  
Primary Objectives 
2.1.1 To compare the overall FLT-PET bone marrow signal on transplant day +25 
between allogeneic stem cell transplant recipients who do and do not go on to 
achieve complete donor bone marrow reconstitution by transplant day +35. 
2.1.2 To compare the overall FLT-PET signal intensity within host secondary lymphoid 
sites on transplant day +60 between allogeneic stem cell transplant recipients who 
do and do not develop acute GVHD by transplant day +100.  
2.2 
Secondary Objectives  
2.2.1 To compare the overall FLT-PET bone marrow signal on transplant day +60 
between allogeneic stem cell transplant recipients who do and do not achieve 
complete donor bone marrow reconstitution by transplant day +100.  
2.2.2 To compare the overall FLT-PET signal intensity within host secondary lymphoid 
sites on transplant day +25 between allogeneic stem cell transplant recipients who 
do and do not develop acute GVHD by transplant day +100  
2.2.3 To evaluate differences in FLT uptake within the bone marrow and secondary 
lymphoid tissues in patients undergoing autologous HSCT versus allogeneic 
HSCT 
2.2.4 To correlate the strength of the FLT-PET signal within the bone marrow on 
transplant day +25 with the rate of transfusion independence on transplant day 
+35 in allogeneic stem cell transplant recipients 
2.2.5 To correlate the strength of the FLT-PET signal within the bone marrow on 
transplant day +25 with bone marrow cellularity on transplant day +35 in 
allogeneic stem cell transplant recipients.  
2.2.6 To correlate the strength of the FLT-PET signal within the bone marrow on 
transplant day +60 with the rate of transfusion independence on transplant day 
+100 in allogeneic stem cell transplant recipients 
 

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2.2.7 To correlate the strength of the FLT-PET signal within the bone marrow on 
transplant day +60 with bone marrow cellularity on transplant day +100 in 
allogeneic stem cell transplant recipients 
2.2.8 To evaluate if isolated or asymmetric foci of increased FLT within the bone 
marrow or lymph nodes on transplant day +60 are associated with the incidence 
of disease relapse by day +100 in allogeneic stem cell transplant recipients 
2.2.9 To correlate the strength of the FLT-PET signal within the bone marrow on 
transplant day +25 and on day +60 with MRI findings suggestive of engraftment 
in allogeneic stem cell transplant recipients     
2.2.10 To evaluate the association of the overall FLT-PET signal intensity within host 
secondary lymphoid sites on transplant day +60 with the overall incidence of 
acute graft versus host disease and malignancy relapse over the first transplant 
year 
2.3 
Primary Endpoints 
2.3.1 The overall FLT-PET bone marrow signal will be defined as the average 
maximum FLT SUV within the vertebrae, pelvis, and bilateral femurs measured 
at the time of early engraftment.  This scan will be obtained on transplant day +25 
+/- 5 days.  Complete donor reconstitution will be defined as chimerisms ≥ 95% 
within the CD3 and unfractionated compartments on bone marrow biopsy/aspirate 
obtained on transplant day +35  
2.3.2 The overall FLT-PET signal within host secondary lymphoid tissue will be 
defined as the average maximum FLT SUV within the spleen, cervical lymph 
nodes, axillary lymph nodes, inguinal lymph nodes, and mesenteric lymph nodes.  
This scan will be obtained on transplant day +60 +/- 5 days.  Acute GVHD will be 
diagnosed either clinically or preferably pathologically within any target organ by 
transplant days +100. 
2.4 
Secondary Endpoints 
2.4.1 The overall FLT-PET bone marrow signal will be defined as the average 
maximum  FLT SUV within the vertebrae, pelvis, and bilateral femurs measured 
on transplant day +60.  Complete donor reconstitution will be defined as 
chimerisms ≥ 95% within the CD3 and unfractionated compartments on bone 
marrow biopsy/aspirate obtained on transplant day +100 
2.4.2 The overall FLT-PET signal within host secondary lymphoid tissue will be 
defined as the average maximum FLT SUV within the spleen, cervical lymph 
nodes, axillary lymph nodes, inguinal lymph nodes, and mesenteric lymph nodes 

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on transplant day +25.  Acute GVHD incidence will diagnosed either clinically or 
preferably pathologically within any target organ by transplant day +100. 
2.4.3 The overall FLT-PET signal within recipient secondary lymphoid tissue (average 
maximum FLT SUV within the spleen, cervical lymph nodes, axillary lymph 
nodes, inguinal lymph nodes, and mesenteric lymph nodes) and the bone marrow 
(average maximum FLT SUV within the vertebrae, pelvis, bilateral femurs) in 
autologous transplant recipients will be compared to the corresponding overall 
FLT-PET signals from allogeneic transplant recipients on transplant days +25 and 
+60. 
2.4.4 Transfusion independence will be defined as not having received a packed red 
blood cell (PRBC) or platelet transfusion within the 7 days preceding the day +35 
or the day +100 time point 
2.4.5 Bone marrow cellularity will be defined in a dichotomous manner as either 
hypocellular or normocellular/hypercellular based on the bone marrow pathology 
report from the day +35 and day +100 bone marrow biopsies. 
2.4.6 The average FLT SUV in the vertebral column will be compared to the 
quantitative T1 and Diffusion Weighted Imaging (DWI) signals in the vertebral 
column by MRI.  The average FLT SUV in the pelvis will be compared to the 
quantitative T1 and Diffusion Weighted Imaging (DWI) signals in the pelvis by 
MRI.  The average FLT SUV in the bilateral femurs will be compared to the 
quantitative T1 and Diffusion Weighted Imaging (DWI) signals in the bilateral 
femurs by MRI.   
 
3.0 
PATIENT ELIGIBILITY 

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3.1 
Inclusion Criteria 
3.1.1 Patients undergoing allogeneic bone marrow transplant for acute myeloid 
leukemia (AML), acute lymphoblastic leukemia (ALL), or myelodysplastic 
syndrome 
3.1.2 Allogeneic transplant patients receiving either a fully myeloablative or reduced 
intensity chemotherapy +/- total body irradiation (TBI) conditioning regimen are 
eligible. 
3.1.3 Allogeneic transplant patients receiving stem cells from a matched related, 
matched unrelated, mismatched unrelated, mismatched related (including 
haplotype matched) donors are eligible   
3.1.4 Allogeneic transplant patients must be in a complete morphologic remission prior 
to transplant 
3.1.5 Patients undergoing autologous bone marrow transplant for multiple myeloma  
3.1.6 Myeloma patients must have achieved at least a very good partial remission prior 
to transplant and exhibit fewer than 10% plasma cells in their pre-transplant 
marrow biopsy 
3.1.7 > 18 years of age 
3.1.8 Able to provide informed consent 
3.1.9 Negative urine pregnancy test in women of child-bearing potential 
3.2 
Exclusion Criteria 
Subjects meeting any of the exclusion criteria at baseline will be excluded from 
participating in this study. 
3.2.1 Any woman who is pregnant or has reason to believe she is pregnant or any 
woman who is lactating.  
3.2.2 Condition that makes MRI unsafe (e.g., cardiac pacemaker, epicardial pacemaker 
leads, cochlear implants, metal aneurysm clip, metal halo devices) 
3.2.3 Inability to tolerate MRI (e.g., unable to lie flat for > 1 hour, severe 
claustrophobia) 
3.2.4 Known allergy to fluorothymidine  
 

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3.2.5 Creatinine clearance < 40 ml/min, as estimated by the Cockcroft-Gault formula: 
 
3.2.6 Poorly controlled diabetes mellitus (fasting blood glucose > 500 mg/dl) 
3.2.7 Institutionalized subject (prisoner or nursing home patient) 
3.2.8 Critically ill or medically unstable.  
3.2.9 Currently hospitalized (All FLT-PET MRI scans will be obtained in the outpatient 
setting) 
4.0 
STUDY PLAN 
4.1 
Study Duration 
It is anticipated that the total study duration encompassing recruitment, 
enrollment, and data analysis will take approximately 2 years.  Active patient 
participation will last approximately 100 days.  Patients will be followed for one 
year for the development of acute GVHD or graft failure. 
4.2 
Schema  
 
 
This is a non-randomized prospective pilot study of patients who have undergone 
either allogeneic or autologous bone marrow transplants.  Subjects will complete 
FLT-PET/MRI scans on transplant day +25 and on day +60 post-transplant.  Only 
allogeneic transplant patients will undergo restaging marrow biopsies on days +35 
and +100 as part of the usual standard of care. 
 
FLT-PET-MRI 
Early 
Engraftment 

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4.3 
Enrollment/Recruitment 
We will plan to enroll a total of 15 patients in this study.  Each patient will be 
asked to undergo two FLT-PET MRI scans as described above.  The study 
patients who meet the eligibility criteria will be recruited by study personnel in 
the UNC Bone Marrow Transplant Program.    
 
Once a patient has been referred, the patient will be approached by a coordinator 
to assess interest in participation. All eligible patients who agree to participate in 
the study will be asked to come to their scheduled appointment thirty minutes 
early to complete the informed consent process.   
 
Review of the consent will take place in the privacy of an exam room, or when 
possible, a sample consent form will be sent to the patient via email prior to the 
patient’s visit to allow for ample review.  Once the patient has consented, women 
of child bearing potential (WCBP) will be given a urine pregnancy test in order to 
ensure that they are not pregnant. 
 
We are currently seeking to perform a total of 30 FLT-PET MRI scans (two each 
on 15 patients).  If, however, a patient(s) drops out of the study after completing 
only a single scan, additional patients may be approached for participation. 
4.4 
FLT-PET/MRI 
Experimental measurements will be obtained at two time points: On transplant 
day +25 +/- 5 days (immediately after neutrophil count recovery) and again on 
transplant day +60 +/- 5 days (a time point after stable count recovery). FLT 
PET/MR imaging will be performed. FLT will be obtained from the BRIC 
Radiochemistry Core. At each FLT-PET-MRI study visit, subjects will complete 
screening forms pertinent to both PET and MR. 
 
A technologist will attempt to access an existing central venous catheter if 
appropriately credentialed personnel are on site.  If necessary, however, a 
peripheral IV line will be placed. The patient will then be brought into the scanner 
room to initiate the scan.   FLT (5 mCi) will be injected one hour prior to imaging 
and dynamic acquisitions will be obtained. Whole body PET/MR will be 
performed with conventional attenuation correction, whole body STIR (node 
identification). The MR portion of the scan will be simultaneously obtained 
without the use of gadolinium contrast agent.   
4.5 
Medical Records Abstraction  
Objectives of this study include identifying quantitative imaging markers that best 
predict engraftment quality and GVHD development in allogeneic HSCT patients.  
To achieve this aim, we will correlate the imaging data with the need for blood 
product transfusion support, biopsy based measures of bone marrow 
donor/recipient chimerism studies and overall bone marrow cellularity, and the 
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Patient pathology records will be obtained after the 100-day follow-up period has 
passed and again one year post-transplant or at the time of death if the patient 
expires prior to then 
 
All patients receiving HSCT have outcomes data collected for quality and 
program performance assessments.  This data is collected for every patient until 
either death or lost to follow-up.  The data routinely collected includes 
demographic data, donor match information, and outcomes of engraftment, 
survival, disease relapse, and development of acute and chronic GVHD.   
Image Analysis 
Quantitative T1 and DWI ADC maps will be computed. Regions of interests 
(ROIs) will be drawn on the anatomic MR images (blinded to SUV values and 
clinical outcome), then transferred to FLT SUV maps. We will correlate the 
imaging data with the histopathological data to identify the quantitative markers 
that best predict engraftment quality. 
5.0 
EXPECTED RISKS/UNANTICIPATED PROBLEMS 
5.1 
Expected Risks 
5.1.1 Risks of PET/MRI 
5.1.1.1 IV Placement 
For patients, study participation may require placement of an IV for 
administration of the radioisotope for PET/MRI scans if we are unable to utilize 
existing central venous access.  IV placement may result in pain, bruising or 
infection.  The IV will be placed by a certified BRIC technologist using sterile 
techniques to minimize the risk of bleeding and infection.  Patients will have the 
option of a topical anesthetic for IV placement to reduce pain and discomfort. 
5.1.1.2 Radiation 
The FLT-PET/MRI scans will expose subjects to controlled amounts of limited 
radiation.  Subjects will be informed of an estimated dose of radiation as specified 
by the Radiation Safety Committee.  The amount of risk to this estimated dose 
will be compared to the annual radiation exposure a typical individual receives on 
a yearly basis from natural background radiation in the informed consent.  This 
radiation exposure involves a small risk and is necessary to obtain the information 
desired. 
 
Risks arising from the imaging procedure itself including injury to the donor bone 
marrow and/or additional infectious complications are felt to be extremely low 
but theoretically possible.  Notably FLT-PET scanning has been applied to both 
the autologous and allogeneic stem cell transplant patient population previously 
with no reported adverse effects on patient outcomes.9,11  Furthermore an NCI 
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allogeneic stem cell transplants as early as 5 days post-transplant (NCI study 
NCT01338987, Pilot Study of Lupron to Improve Immune Function After 
Allogeneic Bone Marrow Transplantation).  Nevertheless, the following 
assessments will be undertaken to carefully monitor for any unexpected effects on 
peripheral blood counts or susceptibility to infection. 
 
5.1.1.2.1 
Allogeneic Transplant Patients 
All allogeneic transplant recipients on study will undergo at least twice weekly 
complete blood count analyses and complete metabolic panels (i.e. blood 
chemistry including electrolytes, serum creatinine and BUN, liver function tests) 
during the first 90 days post-transplant.  All allogeneic transplant recipients on 
study will also undergo weekly quantitative viral loads for CMV and EBV.  
Additional infectious testing will be obtained as clinically indicated.  Notably, all 
of these evaluations are already obtained for all allogeneic stem cell transplant 
patients at The University of North Carolina as part of the standard of care.  It is 
routine practice at UNC for all allogeneic transplant recipients to be seen 2-3 
times weekly in the bone marrow transplant clinic over the entire first 100 days 
post-transplant. 
 
5.1.1.2.2 
Autologous Transplant Patients 
Autologous transplant patients on study will undergo at least two complete blood 
count analyses and two complete metabolic panels during the week immediately 
following their first scan, and at least one CBC and one comprehensive metabolic 
panel following their second scan.  Since the second scan will be obtained many 
weeks after count recovery, any risk to the donor bone marrow product is 
considered to be even less at this time point, and hence only a single set of labs is 
mandated.  As CMV and EBV reactivation are extremely rare in the autologous 
transplant patients, viral loads for these agents will not be mandated.  Rather, any 
relevant infectious work-up will be guided by the clinical circumstances. 
5.1.1.3 FLT 
FLT will be available through the Biomedical Research Imaging Center 
Radiopharmaceutical Laboratory as an investigational drug under and National 
Cancer Institute NCI IND. The associated risks and drug details are listed in 
Appendix A.  
5.1.2 Patient Confidentiality 
The risk of breach of confidentiality is low and will be minimized by securing all 
identifiable data in locked cabinets and password-protected electronic medical 
records.  Imaging data will be de-identified during acquisition, labeled with a 
study ID and post-processed on secure computers.  
6.0 
TIME AND EVENTS TABLE 

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6.1 
Time and Events Table 
         
 
 
7.0 
ADVERSE EVENTS  
7.1 
Definition 
7.1.1 Adverse Event (AE) 
An adverse event (AE) is any untoward medical occurrence (e.g., an abnormal 
laboratory finding, symptom, or disease temporally associated with the use of a 
medicinal product, in this case the FLT radiotracer) in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment.  An AE can therefore be 
any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not related to the medicinal product.   
 
Hospitalization for elective surgery or routine clinical procedures that are not the 
result of an AE (e.g., surgical insertion of central line) need not be considered 
AEs and should not be recorded as an AE.  Disease progression should not be 
recorded as an AE, unless it is attributable by the investigator to the study therapy. 
 
As defined by UNC’s IRB, unanticipated problems involving risks to study 
subjects or others (UPIRSO) refers to any incident, experience, or outcome that: 
• 
Is unexpected (in terms of nature, severity, or frequency) given (a) the 
research procedures that are described in the protocol-related documents, 
such as the IRB-approved research protocol and informed consent 
 
Baseline 
+25 after BMT 
+/- 5 days 
35 days 
after BMT 
+/- 5 days 
+60 days 
after BMT 
+/- 5 days 
100 days 
after 
BMT 
+/- 5 
days 
Screening 
X 
 
 
 
 
Informed Consent 
X 
 
 
 
 
FLT-PET-MR 
 
X 
 
X 
 
Standard of Care 
Bone Marrow 
Biopsya 
 
 
X 
 
X 
 
a Allogeneic transplant patients only 
 
 

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document; and (b) the characteristics of the subject population being 
studied; 
• 
Is related or possibly related to a subject’s participation in the research; 
and  
• 
Suggests that the research places subjects or others at a greater risk of 
harm (including physical, psychological, economic, or social harm) related 
to the research than was previously known or recognized. 
7.1.2 A suspected adverse reaction (SAR) is any AE for which there is a reasonable 
possibility that the drug/radiotracer is the cause.   Reasonable possibility means 
that there is evidence to suggest a causal relationship between the drug/radiotracer 
and the AE.  A suspected adverse reaction implies a lesser degree of certainty 
about causality than adverse reaction, which means any adverse event caused by a 
drug/radiotracer.   
 
Causality assessment to a study drug/radiotracer is a medical judgment made in 
consideration of the following factors: temporal relationship of the AE to study 
drug/radiotracer exposure, known mechanism of action or side effect profile of 
study treatment, other recent or concomitant drug exposures, normal clinical 
course of the disease under investigation, and any other underlying or concurrent 
medical conditions.  Other factors to consider in considering drug/radiotracer as 
the cause of the AE: 
• Single occurrence of an uncommon event known to be strongly associated 
with drug/radiotracer exposure (e.g., angioedema, hepatic injury, Stevens-
Johnson Syndrome) 
• One or more occurrences of an event not commonly associated with 
drug/radiotracer exposure, but otherwise uncommon in the population 
(e.g., tendon rupture); often more than once occurrence from one or 
multiple studies would be needed before the investigator could determine 
that there is reasonable possibility that the drug/radiotracer caused the 
event.   
• An aggregate analysis of specific events observed in a clinical trial that 
indicates the events occur more frequently in the treatment group than in a 
concurrent or historical control group 
7.1.3 Unexpected AE or SAR 
An AE or SAR is considered unexpected if the specificity or severity of it is not 
consistent with the applicable product information (e.g., Investigator’s Brochure 
(IB) for an unapproved investigational product or package insert/summary of 
product characteristics for an approved product).  Unexpected also refers to AEs 
or SARs that are mentioned in the IB as occurring with a class of 
drugs/radiotracers or as anticipated from the pharmacological properties of the 
drug/radiotracer, but are not specifically mentioned as occurring with the 
particular agent under investigation.   

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7.1.4 Serious AE or SAR 
An AE or SAR is considered serious if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes: 
• Death; 
• Is life-threatening (places the subject at immediate risk of death from 
the event as it occurred); 
• Requires inpatient hospitalization (>24 hours) or prolongation of 
existing hospitalization;* 
• Results in congenital anomaly/birth defect; 
• Results in a persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions; 
• Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered a serious 
adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed 
in the definition.  For reporting purposes, also consider the occurrences 
of pregnancy as an event which must be reported as an important 
medical event. 
 
*Hospitalization for anticipated or protocol specified procedures such as 
administration of chemotherapy, central line insertion, metastasis interventional 
therapy, resection of primary tumor, or elective surgery, will not be considered 
serious adverse events. 
 
Pregnancy that occurs during the study must also be reported as an SAE. 
7.2 
Documentation of non-serious AEs or SARs 
For non-serious AEs or SARs, documentation must begin from day 1 of study 
treatment and continue through the 30 day follow-up period after treatment is 
discontinued, in this case the second planned FLT-PET MRI scan.  
 
Collected information should be recorded in the Case Report Forms (CRF) for 
that patient.  Please include a description of the event, its severity or toxicity 
grade, onset and resolved dates (if applicable), and the relationship to the study 
drug. Documentation should occur at least monthly.  
7.3 
SAEs or Serious SARs 
7.3.1 Timing 
After informed consent but prior to initiation of study medications/radiotracer 
administration, only SAEs caused by a protocol-mandated intervention will be 
collected (e.g. SAEs related to invasive procedures such as biopsies, medication 
washout).  
 

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For any other experience or condition that meets the definition of an SAE or a 
serious SAR, recording of the event must begin from day 1 of study treatment and 
continue through the 30 day follow-up period after treatment is discontinued, in 
this case the second planned FLT-PET MRI scan.  
7.3.2  Documentation and Notification 
SAEs or Serious SARs must be recorded in the SAE console within Oncore™ for 
that patient within 24 hours of learning of its occurrence.  Additionally, the 
NCCN Project Manager must also be notified via email of all SAEs within 24 
hours of learning of its occurrence.  
7.3.3 Reporting  
IRB Reporting Requirements: 
UNC: 
UNC will submit an aggregated list of all SAEs to the UNC IRB annually at 
the time of study renewal according to the UNC IRB policies and 
procedures. 
The UNC-IRB will be notified of all SAEs that qualify as an Unanticipated 
Problem as per the UNC IRB Policies using the IRB’s web-based 
reporting system (see section 9.5.3) within 7 days of the Investigator 
becoming aware of the problem.   
 
Pregnancy 
Pregnancies and suspected pregnancies (including a positive pregnancy test 
regardless of age or disease state) of a female subject occurring while the subject 
is on study should be recorded as SAEs.  The patient is to be discontinued 
immediately from the study. The female subject should be referred to an 
obstetrician-gynecologist, preferably one experienced in reproductive toxicity for 
further evaluation and counseling. 
 
The Investigator will follow the female subject until completion of the pregnancy, 
and must document the outcome of the pregnancy (either normal or abnormal 
outcome) and report the condition of the fetus or newborn to the UCCN Project 
Manager. If the outcome of the pregnancy was abnormal (e.g., spontaneous or 
therapeutic abortion), the Investigator should report the abnormal outcome as an 
AE. If the abnormal outcome meets any of the serious criteria, it must be reported 
as an SAE.   
 
 
FDA Expedited Reporting requirements for studies conducted under an IND: 
If an investigator deems that an event is both a serious SAR AND unexpected, it 
must also (in addition to Oncore) be recorded on the MedWatch Form 3500A as per 
21 CFR 312.32.  Unexpected adverse events or adverse reaction refers to an event 
or reaction that is not listed in the investigator’s brochure or is not listed at the 
specificity or severity that has been observed; or if an investigator’s brochure is not 

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required or available, is not consistent with the risk information described in the 
general investigation plan or elsewhere in the current IND application.   
 
The MedWatch form should be faxed to the UNCCN Project Manager at 919-966-
4300 (or emailed, with address provided at the Start up Meeting (SIM)) along with 
supporting documentation defining the event and causality.  The UNCCN Project 
Manager will then send the report to the Funding Source.  
 
Once the UNC Principal Investigator determines an event is a serious SAR AND 
unexpected, the MedWatch 3500A form will be submitted to the FDA by the 
UNCCN Project Manager.  If the event is serious, unexpected and considered to be 
possibly-, probably- or definitely-related to the study treatment, the UCCN Project 
Manager will inform the Regulatory Associate at UNC who will be responsible for 
submitting the SAR to the IND. All IND safety reports must be submitted on Form 
3500A and be accompanied by Form 1571. The FDA must be notified or any 
unexpected or life-threatening suspected adverse reactions as soon as possible, but 
no later than 7 calendar days of learning of the event. 
 
The UNCCN Project Manager will also be responsible for informing each Affiliate 
site of all serious and unexpected SARs reported to the FDA via fax as soon as 
possible.   
7.4 
Data and Safety Monitoring Plan 
The Principal Investigator will provide continuous monitoring of patient safety in 
this trial. 
Meetings/teleconferences will be held at a frequency dependent on study accrual, 
and in consultation with the study Biostatistician.  These meetings will include the 
investigators as well as protocol nurses, clinical research associates, regulatory 
associates, data managers, biostatisticians, and any other relevant personnel the 
principal investigators may deem appropriate.  At these meetings, the research 
team will discuss all issues relevant to study progress, including enrollment, 
safety, regulatory, data collection, etc. 
The team will produce summaries or minutes of these meetings. These summaries 
will be available for inspection when requested by any of the regulatory bodies 
charged with the safety of human subjects and the integrity of data including, but 
not limited to, the oversight (Office of Human Research Ethics (OHRE) 
Biomedical IRB, the Oncology Protocol Review Committee (PRC) or the North 
Carolina TraCS Institute Data and Safety Monitoring Board (DSMB).   
The UNC LCCC Data and Safety Monitoring Committee (DSMC) will review the 
study on a regular (quarterly to annually) basis, with the frequency of review 
based on risk and complexity as determined by the UNC Protocol Review 
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information for review: 1) safety and accrual data including the number of 
patients treated; 2) significant developments reported in the literature that may 
affect the safety of participants or the ethics of the study; 3) preliminary response 
data; and 4) summaries of team meetings that have occurred since the last report.  
Findings of the DSMC review will be disseminated by memo to the UNC PI, 
PRC, and the UNC IRB and DSMB.  
8.0 
STATISTICAL CONSIDERATIONS 
8.1 
Study Design 
This is a non-randomized, prospective pilot study exploring the use of FLT-PET-
MRI in the evaluation of allogeneic patients after bone marrow transplants to 
potentially predict engraftment success and the development of graft versus host 
disease. A total of 15 patients who have undergone bone marrow transplantation 
will receive FLT-PET-MRI imaging, 3 autologous and 12 allogenic recipients 
will be recruited.  The 3 autologous patients are included as a comparator arm to 
help elucidate how much of the FLT signal in allogeneic HSCT patients is related 
to allo-antigen driven T cell proliferation and therefore unique to the allogeneic 
setting.   
8.2 
Sample Size and Accrual 
This is a pilot study to gather preliminary data, and the results from this study will 
be used to power a future larger R01.  However, we will have power to detect 
large differences between groups as follows. For power calculation, the null 
hypothesis is that there will be no difference in the FLT bone marrow signal 
between those allograft patients demonstrating incomplete and complete donor 
reconstitution on their restaging marrow biopsies, and no difference in the FLT 
signal within secondary lymphoid tissues between patients with and without acute 
GVHD. 
 
Complete Donor Reconstitution: 
Considering only the 12 allogeneic patients, we will compare the mean FLT bone 
marrow signal between those with and without complete donor reconstitution.  In 
general we would expect approximately 50-70% of our patients overall to achieve 
complete donor reconstitution in both the unfractionated and CD3 enriched 
compartments by transplant day +30. 
 
Assuming equal number of patients with/without Complete Donor Reconstitution: 
 
A sample size of 6 in each group will have 80% power to detect a probability of 
0.854 that an observation in the Complete Donor Reconstitution group is less than 
an observation in the non-Complete Donor Reconstitution group using a 
Wilcoxon (Mann-Whitney) rank-sum test with a 0.100 one-sided significance 
level. 
 

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Assuming unequal number of patients with/without Complete Donor 
Reconstitution: 
 
A total sample size of 12 will have 80% power to detect a probability of 0.87 that 
an observation in the Complete Donor Reconstitution group (n=7) is less than an 
observation in the non-Complete Donor Reconstitution group (n=5) using a 
Wilcoxon (Mann-Whitney) rank-sum test with a 0.100 one-sided significance 
level. 
 
Graft Versus Host Disease:  
Considering only the 12 allogeneic patients, we will compare the mean FLT 
signal within secondary lymphoid tissues in those patients who develop acute 
GVHD versus those who do not based on the criteria described previously.  In 
general we would expect that approximately 30-40% of our patients will develop 
some degree of acute GVHD (any site and any clinical grade) by transplant day 
+100 
 
A sample size of 6 in each group will have 80% power to detect a probability of 
0.854 that an observation in the non-GVHD group is less than an observation in 
the GVHD group using a Wilcoxon (Mann-Whitney) rank-sum test with a 0.100 
one-sided significance level. 
 
8.3 
Data Analysis Plans 
8.3.1 Primary Analysis 
 
Experimental measurements will be obtained at two time points: around day +21 
(at the time of initial neutrophil engraftment) and around day +60 (after stable 
count recovery). FLT standardized uptake value (SUV) will be evaluated within 
the following target organs: The marrow signal will be evaluated in the pelvis, 
vertebrae, and bilateral femurs.  The secondary lymphoid tissue signal will be 
evaluated in the spleen, inguinal lymph nodes, axillary lymph nodes, cervical 
lymph nodes, and mesenteric lymph nodes).  We will plan to image 3 autograft 
and 12 allograft patients.   
 
Wilcoxon Rank sum tests will be used to compare signals between the groups. 
Spearman and Pearson correlation coefficients will be used to measure 
correlations between pairs of continuous variables.    ROC analyses will be 
performed to explore the sensitivity/specificity of signal ratio cutoffs for the 
outcomes of Complete Donor Reconstitution and GVHD.   
 
8.4 
Data Management/Audit 
The images of all eligible enrolled subjects that are obtained will be de-identified 
for inclusion in the reader study. Copies of the clinical report forms as well as the 

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de-identified images described in the preceding will be submitted for each case to 
the Study Coordinators for maintaining the study record and entering the data into 
a spreadsheet in preparation for the reader study. 
  
As an investigator initiated study, this trial may also be audited by the Lineberger 
Cancer Center audit committee every twelve months. 
9.0 
STUDY MANAGEMENT 
9.1 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations.  The IRB should approve the 
consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply 
with the applicable regulatory requirement(s), and should adhere to Good Clinical 
Practice (GCP) and to ethical principles that have their origin in the Declaration 
of Helsinki. 
 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent 
form. Each consent form must include all the relevant elements currently required 
by the FDA Regulations and local or state regulations. Once this essential 
information has been provided to the patient and the investigator is assured that 
the patient understands the implications of participating in the study, the patient 
will be asked to give consent to participate in the study by signing an 
IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form 
should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion. 
9.2 
Required Documentation 
Before the study can be initiated at any site, the following documentation must be 
provided to the Clinical Protocol Office (CPO) at the University of North 
Carolina. 
 
• A copy of the official IRB approval letter for the protocol and 
informed consent 
• CVs and medical licensure for the principal investigator and any 
associate investigators who will be involved in the study 
• A copy of the IRB-approved consent form 
 

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9.3 
Registration Procedures 
Patients will be registered into OnCore®, a web based clinical research platform 
by one of the Study Coordinators.  The spread sheet contains each subject 
enrolled in the study identified by the patient first and last initial, study id, date of 
enrollment into study, race and ethnicity.  
9.4 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, 
and well-being of the study patient requires alternative treatment, the study shall 
be conducted exactly as described in the approved protocol.   
9.4.1 Emergency Modifications 
UNC investigators may implement a deviation from, or a change of, the protocol 
to eliminate an immediate hazard(s) to trial subjects without prior UNC IRB 
approval.  
 
For any such emergency modification implemented, a UNC IRB modification 
form must be completed by UNC Research Personnel within five (5) business 
days of making the change.   
9.4.2 Single Patient/Subject Exceptions 
Any request to enroll a single subject who does not meet all the eligibility criteria 
of this study requires the approval of the UNC Principal Investigator and the UNC 
IRB.  
9.4.3 Other Protocol Deviations/Violations 
According to UNC’s IRB, a protocol deviation is any unplanned variance from an 
IRB approved protocol that:  
• Is generally noted or recognized after it occurs 
• Has no substantive effect on the risks to research participants 
• Has no substantive effect on the scientific integrity of the research plan 
or the value of the data collected  
• Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
An unplanned protocol variance is considered a violation if the variance meets 
any of the following criteria:  
• Has harmed or increased the risk of harm to one or more research 
participants. 
• Has damaged the scientific integrity of the data collected for the study. 
• Results from willful or knowing misconduct on the part of the 
investigator(s). 
• Demonstrates serious or continuing noncompliance with federal 
regulations, State laws, or University policies. 
 

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If a deviation or violation occurs please follow the guidelines below: 
 
Protocol Deviations: UNC personnel will record the deviation in OnCore®  (or 
other appropriate database set up for the study), and report to any sponsor or data 
and safety monitoring committee in accordance with their policies.  Deviations 
should be summarized and reported to the IRB at the time of continuing review. 
 
Protocol Violations: Violations should be reported by UNC personnel within one 
(1) week of the investigator becoming aware of the event using the same IRB 
online mechanism used to report UPIRSO.   
 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSO: 
Any events that meet the criteria for “Unanticipated Problems” as defined by 
UNC’s IRB (see section 6.1) must be reported by the Study Coordinator using the 
IRB’s web-based reporting system.   
• Has damaged the scientific integrity of the data collected for the study. 
9.5 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be 
originated and documented by the Principal Investigator at UNC.  It should also 
be noted that when an amendment to the protocol substantially alters the study 
design or the potential risk to the patient, a revised consent form might be 
required.   
 
The written amendment, and if required the amended consent form, must be sent 
to UNC’s IRB for approval prior to implementation.   
9.6 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or 
queries, source documents, Sponsor-Investigator correspondence, monitoring 
logs/letters, and regulatory documents (e.g., protocol and amendments, IRB 
correspondence and approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and 
reconstruction of the clinical research study. 
 
Government agency regulations and directives require that all study 
documentation pertaining to the conduct of a clinical trial must be retained by the 
study investigator.  In the case of a study with a drug seeking regulatory approval 
and marketing, these documents shall be retained for at least two years after the 
last approval of marketing application in an International Conference on 
Harmonization (ICH) region.  In all other cases, study documents should be kept 
on file until three years after the completion and final study report of this 
investigational study. 

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9.7 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the 
site in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki.  The Principal Investigator is responsible for personally 
overseeing the treatment of all study patients.  The Principal Investigator must 
assure that all study site personnel, including sub-investigators and other study 
staff members, adhere to the study protocol and all FDA/GCP/NCI regulations 
and guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for 
assuring that all the required data will be collected and entered onto the Case 
Report Forms. Periodically, monitoring visits will be conducted and the Principal 
Investigator will provide access to his/her original records to permit verification 
of proper entry of data. At the completion of the study, all case report forms will 
be reviewed by the Principal Investigator and will require his/her final signature 
to verify the accuracy of the data. 
 
 
 

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10.0 REFERENCES 
1.  Wysocki CA, Panoskaltsis-Mortari A, Blazar BR, Serody JS. Leukocyte migration 
and graft-versus-host disease. Blood. 2005 Jun 1;105(11):4191–4199. PMCID: 
PMC1895033 
2.  Shlomchik WD, Couzens MS, Tang CB, McNiff J, Robert ME, Liu J, Shlomchik MJ, 
Emerson SG. Prevention of graft versus host disease by inactivation of host antigen-
presenting cells. Science. 1999 Jul 16;285(5426):412–415. PMID: 10411505 
3.  Beilhack A, Schulz S, Baker J, Beilhack GF, Nishimura R, Baker EM, Landan G, 
Herman EI, Butcher EC, Contag CH, Negrin RS. Prevention of acute graft-versus-
host disease by blocking T-cell entry to secondary lymphoid organs. Blood. 2008 
Mar 1;111(5):2919–2928. PMCID: PMC2254542 
4.  Anderson BE, Taylor PA, McNiff JM, Jain D, Demetris AJ, Panoskaltsis-Mortari A, 
Ager A, Blazar BR, Shlomchik WD, Shlomchik MJ. Effects of donor T-cell 
trafficking and priming site on graft-versus-host disease induction by naive and 
memory phenotype CD4 T cells. Blood. 2008 May 15;111(10):5242–5251. PMCID: 
PMC2384145 
5.  Zhuang H, Alavi A. 18-fluorodeoxyglucose positron emission tomographic imaging 
in the detection and monitoring of infection and inflammation. Semin Nucl Med. 
2002 Jan;32(1):47–59. PMID: 11839069 
6.  Almuhaideb A, Papathanasiou N, Bomanji J. 18F-FDG PET/CT Imaging In 
Oncology. Ann Saudi Med. 2011;31(1):3–13. PMCID: PMC3101722 
7.  Shields AF, Grierson JR, Dohmen BM, Machulla H-J, Stayanoff JC, Lawhorn-Crews 
JM, Obradovich JE, Muzik O, Mangner TJ. Imaging proliferation in vivo with [F-
18]FLT and positron emission tomography. Nat Med. 1998 Nov;4(11):1334–1336.  
8.  Awasthi V, Holter J, Thorp K, Anderson S, Epstein R. F-18-fluorothymidine-PET 
evaluation of bone marrow transplant in a rat model. Nucl Med Commun. 2010 
Feb;31(2):152–158. PMID: 19966596 
9.  Woolthuis C, Agool A, Olthof S, Slart RHJA, Huls G, Smid WM, Schuringa JJ, 
Vellenga E. Auto-SCT induces a phenotypic shift from CMP to GMP progenitors, 
reduces clonogenic potential and enhances in vitro and in vivo cycling activity 
defined by 18F-FLT PET scanning. Bone Marrow Transplant. 2011 Jan;46(1):110–
115.  
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A Novel Technique to Analyze the Bone Marrow Compartment. J Nucl Med. 2006 
Oct 1;47(10):1592–1598. PMID: 17015893 

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11.  Agool A, Slart RHJA, Kluin PM, de Wolf JTM, Dierckx RAJO, Vellenga E. F-18 
FLT PET: A Noninvasive Diagnostic Tool for Visualization of the Bone Marrow 
Compartment in Patients With Aplastic Anemia: A Pilot Study. Clin Nucl Med. 2011 
Apr;36(4):286–289.  
 
 
 
 
 

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11.0 APPENDICES 
Appendix A:  FLT 
1.1 Chemical Name  
 
3'-deoxy-3'-18F fluorothymidine (FLT)    
 
1.2 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  
 
1.3 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 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 

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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 (≥ 10 mg) of FLT for several weeks (See 
Section 9.1.10). In comparison, the proposed 18F-FLT PET studies use a maximum injection 
of 10µg, a factor of 1,000 times lower50. 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. 
 
1.4 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 Washington51. 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.  
The first scenario is conservative, whereas the second has a more realistic voiding scheme.   
 
1.5 Previous human  [18F]FLT imaging studies 

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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.  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). 
 
1.6 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 6.2, 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 3.3 and is 
comparable to the dose for other widely used clinical nuclear medicine procedures.  
 
1.7 [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]FLT for most studies will be ≤  
0.07 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 of injected drug is  ≤ 6.1 µg (≤ 25 nmol per dose) of 
FLT.   [18F]FLT is administered to subjects by intravenous injection of ≤ 10 mL.  There is no 
evidence that nonradioactive and radioactive FLT molecules display different biochemical 
behavior. 
 
1.8 Agent Availability 
[18F]FLT will be provided by the Biomedical Research Imaging Radiopharmaceutical Core  
under an IND held by the Cancer Imaging Program (CIP)/NCI. The cross reference letter has 
been obtained.  
 
 
 

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Appendix B: Reader Study Data Collection Form 
 
Patient ID:   
 
 
 
 
 
 
Reader: 
 
 
 
 
Date:  
 
 
 
Overall Assessment: 
 
 
  
 
 
 
 
FLT SUV in pelvis ____________ 
 
FLT SUV in vertebrae ____________ 
 
FLT SUV in right femur ____________ 
 
FLT SUV in left femur _____________ 
 
FLT SUV in inguinal lymph nodes ___________ 
 
FLT SUV in axillary lymph nodes ____________ 
 
FLT SUV in cervical lymph nodes _____________ 
 
FLT SUV in mesenteric lymph nodes ___________