Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment
Phase: PHASE2
Conditions: Breast Cancer
Sponsor: University of Utah

PI: Jeffrey Yap, PhD  
 
     Page 1 of 73 
Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
Version Date: 03/21/2024 
 
 
University of Utah IRB  
Document Version:  010312 
 
Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment (CICI) 
Version Date: 03/21/2024 
 
Principal Investigator 
Jeffrey Yap, PhD 
Director, Center for Quantitative Cancer Imaging 
Research Professor, University of Utah School of Medicine 
    
1950 Circle of Hope  
Suite 6720 
Salt Lake City, UT 84112-5550 
Telephone: (801) 213-5650 
Jeffrey.Yap@hci.utah.edu 
 
 
 
Partial Financial Support is provided by GE Healthcare 
 
 
Imaging Agents to be used: 
 
[18F]Flutemetamol: IND# - 109,760 (FDA approved as Vizamyl 10/25/13)1 
 
[18F]fluoro-2-deoxy-D-glucose (FDG): IND# - 113,858 
 
 
 
University of Utah IRB # 00069515 
 
 
 

PI: Jeffrey Yap, PhD  
 
     Page 2 of 73 
Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
Version Date: 03/21/2024 
 
 
University of Utah IRB  
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Table of Contents 
1. OBJECTIVES ................................................................................................................................ 6 
1.1 Purpose of Study .................................................................................................................... 6 
1.2 Primary Objective of Study - Synopsis ................................................................................ 6 
1.3 
Hypotheses to be Tested - Synopsis ................................................................................ 6 
2. BACKGROUND ........................................................................................................................... 7 
2.1 Review of Previous Research ................................................................................................ 9 
2.2 NEUROPSYCH ASSESSMENTS FOR CICI................................................................... 13 
2.3 MRI IMAGING IN PATIENTS WITH CICI ................................................................... 14 
2.4 [18F]FLUTEMETAMOL as an IMAGING AGENT ........................................................ 14 
2.5 [18F]-FDG as an IMAGING AGENT ................................................................................. 15 
3. PHARMACOLOGY, METABOLISM, AND BIODISTRIBUTION OF 
[18F]FLUTEMETAMOL ................................................................................................................ 16 
3.1 Pharmacology of [18F]Flutemetamol .................................................................................. 16 
3.2 Dosage form .......................................................................................................................... 16 
3.3 In vitro Metabolism and Plasma Protein Binding of [18F]Flutemetamol ........................ 17 
3.4 In vivo Metabolism of [18F]Flutemetamol .......................................................................... 18 
4. TOXICITY and SAFETY OF FLUTEMETAMOL (as described in the [18F]Flutemetamol  
Investigator’s Brochure and Vizamyl Package Insert)1 ................................................................... 18 
4.1 Flutemetamol Toxicology .................................................................................................... 18 
4.2 Previous Human Studies with [18F]Flutemetamol ............................................................ 19 
4.2.1 ALZ101 Study ................................................................................................................... 21 
4.2.2 ALZ102 Study ................................................................................................................... 23 
4.2.3 ALZ103 Study ................................................................................................................... 26 
5. TOXICITY and SAFETY OF FDG ............................................................................................. 28 
5. 1 Safety and Toxicity of FDG in Humans ............................................................................ 28 
6. Radiation Dosimetry of [18F]FLUTEMETAMOL and FDG PET/ ............................................ 29 
6.1 Human Radiation Dosimetry for [18F]Flutemetamol ....................................................... 29 
6.2 Human Radiation Dosimetry for [18F]FDG ....................................................................... 29 
6.3 Human Radiation Dosimetry for CT-based Attenuation Correction for PET Imaging 29 
6.4 Cumulative Radiation Dosimetry for [18F]Flutemetamol and [18F]FDG PET/CT Studies
...................................................................................................................................................... 30 
7. RATIONALE, GOALS, AND HYPOTHESES .......................................................................... 30 
7.1 Rationale and Goals of Study.............................................................................................. 30 
7.2 Significance ........................................................................................................................... 31 
7.3 Primary Endpoint ................................................................................................................ 31 
7.4 Exploratory Endpoints ........................................................................................................ 31 
8. STUDY DESIGN......................................................................................................................... 31 
8.1 Overview of Study Design ................................................................................................... 31 
8.2 Participant Eligibility .......................................................................................................... 32 
8.3 Inclusion Criteria ................................................................................................................. 32 
8.4 Exclusion Criteria ................................................................................................................ 32 

PI: Jeffrey Yap, PhD  
 
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Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
Version Date: 03/21/2024 
 
 
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8.5 Participant Registration ...................................................................................................... 33 
9 STUDY PROCEDURES, SCHEDULE of EVENTS, and TRACER ADMINISTRATION ...... 33 
9.1 Initial Visits Prior to PET Imaging .................................................................................... 33 
9.2 Genetic Analysis ................................................................................................................... 33 
9.3 Neuropsychological Exams ................................................................................................. 34 
9.4 Functional MRI Imaging ..................................................................................................... 34 
9.5 PET Exams ........................................................................................................................... 37 
9.5.1 Day of Research PET Scan(s) ......................................................................................... 37 
9.5.2 PET Tracer Administration Overview ............................................................................ 37 
9.6 Tissue Collection and Analysis ........................................................................................... 38 
10. METHODS FOR EVALUATION OF IMAGING STUDIES/ DATA ANALYSIS AND 
STATISTICS ................................................................................................................................... 38 
10.1 18F-FDG-PET Imaging ...................................................................................................... 38 
10.1.1 FDG Semi-Quantitative Assessment ............................................................................ 38 
10.1.2 FDG Fully-Quantitative Assessment ............................................................................ 39 
10.2 [18F]Flutemetamol-PET Imaging ...................................................................................... 39 
10.3 Magnetic Resonance Imaging ........................................................................................... 40 
10.4 Data Analysis ...................................................................................................................... 40 
10.5 Justification of Sample Size............................................................................................... 41 
11. REGULATORY AND REPORTING REQUIREMENTS ....................................................... 41 
11.1 Expedited Adverse Event Reporting ................................................................................ 42 
11.2 Expedited Reporting Guidelines – Phase 1/2 studies with Investigational Agents ...... 42 
11.3 Expedited Expected Adverse Event Reporting Exclusions ............................................ 43 
11.4 Data Reporting ................................................................................................................... 44 
11.5 Reporting Protocol Violations/Deviations ....................................................................... 44 
12. ETHICAL AND REGULATORY REQUIREMENTS ............................................................. 44 
12.1 Informed consent ............................................................................................................... 44 
12.2 Institutional Review ........................................................................................................... 45 
12.3 Reported Adverse Events and Potential Risks ................................................................ 45 
12.4 Agent Accountability ......................................................................................................... 46 
12.4.1 [18F]Flutemetamol ........................................................................................................... 46 
12.4.2 [18F]FDG .......................................................................................................................... 46 
13. REFERENCES .......................................................................................................................... 47 
14.    APPENDICES ........................................................................................................................ 56 
APPENDIX A:  Eligibility Check List and Current Drug Use and Potential Toxicities .... 57 
Appendix B: Current Drug Use and Potential Toxicities....................................................... 60 
APPENDIX C: MRI Patient History and Safety Screening .................................................. 61 
APPENDIX D:  Schedule of Events ......................................................................................... 63 
APPENDIX E: [18F]Flutemetamol Patient Adverse Event Questionnaire ........................... 65 
APPENDIX F:  NCI Common Toxicity Criteria .................................................................... 66 
APPENDIX G:  GE Healthcare Pregnancy Reporting Form ................................................ 67 
APPENDIX H:  GE Healthcare SAE Reporting Form .......................................................... 68 

PI: Jeffrey Yap, PhD  
 
     Page 4 of 73 
Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
Version Date: 03/21/2024 
 
 
University of Utah IRB  
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APPENDIX I:  GE Healthcare Supplemental Safety Reporting Form ................................ 72 
 
 
 

PI: Jeffrey Yap, PhD  
 
     Page 5 of 73 
Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
Version Date: 03/21/2024 
 
 
University of Utah IRB  
Document Version:  010312 
STUDY SUMMARY 
Title 
Amyloid Deposition in Chemotherapy-Induced Cognitive Impairment 
IRB Protocol Number 
69515 
IND 
[18F]Flutemetamol IND# 109,760 (Yap)  
[18F]fluoro-2-deoxy-D-glucose: FDG IND# 113,858 (Yap) 
Phase 
Phase II 
Design 
Three imaging sessions will be required: 1) [18F]Flutemetamol-PET/CT, 2) FDG-
PET/CT, and 3) MRI.   
Study Duration 
36 Months 
Study Center(s) 
Huntsman Cancer Institute, University of Utah 
Objectives 
The exploratory objective of this study is to determine the association of amyloid 
plaque burden determined with [18F]Flutemetamol-PET imaging, brain 
metabolism determined with FDG, and the anatomical information obtained with 
MRI and correlate these variables in breast cancer patients experiencing 
chemotherapy induced cognitive impairment (CICI). 
Number of Subjects 
15 
Diagnosis and Main 
Eligibility Criteria 
Female adults (18 years or older) with a histologically proven Stage I through 
IIIC Breast Cancer, who are reporting cognitive impairment as a result of 
undergoing adjuvant chemotherapy. 
Study Product, Dose, 
Route, Regimen 
[18F]Flutemetamol is an FDA approved radiopharmaceutical (Vizamyl) that is 
produced in the cyclotron facility at the Huntsman Cancer Institute for research 
purposes under IND #109,760.  
 
FDG is an FDA approved radiopharmaceutical that is produced in the cyclotron 
facility at the Huntsman Cancer Institute for research purposes under IND # 
113,858. 
 
 
 

PI: Jeffrey Yap, PhD  
 
     Page 6 of 73 
Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
Version Date: 03/21/2024 
 
 
University of Utah IRB  
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1. OBJECTIVES 
1.1 Purpose of Study 
This exploratory study uses [18F]Flutemetamol and [18F]fluoro-2-deoxy-D-glucose (FDG) 
investigational positron emission tomography (PET) imaging agents, anatomic magnetic resonance 
imaging (MRI), and functional magnetic resonance imaging (fMRI) in breast cancer patients 
experiencing Chemotherapy-Induced Cognitive Impairment (CICI) to examine possible brain 
related changes. It is anticipated that we will enroll up to 15 women who have been diagnosed with 
breast cancer, completed chemotherapy, and are experiencing CICI, commonly referred to as 
“chemobrain.” The goal is to complete the study in approximately 36 months.  
 
1.2 Primary Objective of Study - Synopsis  
The exploratory objective of this study is to determine the association of amyloid plaque burden 
determined with [18F]Flutemetamol PET imaging, brain metabolism determined with FDG, and the 
anatomical and functional information obtained with fMRI and correlate these variables in 12 
breast cancer patients experiencing CICI. We expect that up to 15 participants may be enrolled in 
this study. This will assure 12 evaluable patients (patients who have complete imaging results and 
blood data available for data analysis). In certain patients the blood data is not acceptable for final 
analysis because of difficulty in drawing it rapidly enough due to the vein collapsing during the 
rapid sampling required. 
 
1.3 Hypotheses to be Tested - Synopsis  
It is our hypothesis that individuals who are experiencing CICI may have a greater than expected 
prevalence of amyloid plaque burden when compared to individuals who are not experiencing 
cognitive complaints. The chemotherapy may accelerate the process of amyloid plaque burden 
deposition and subsequent possible neuronal injury and loss in individuals who have undergone 
chemotherapy.  
 
The initial goal of our interdisciplinary group of imagers, oncologists, neurologists, neuro-
psychologists, and biostatisticians is to obtain “proof of concept” pilot data for eventual 
submission of a National Cancer Institute Quick-Trial for Imaging and Image-Guided 
Interventions: Exploratory Grant (R10) depending on the results of this pilot study.  
 
The overall objective is to use [18F]Flutemetamol, FDG-PET, and fMRI to better understand CICI, 
which effects up to 16 -50% of individuals receiving long-term adjuvant chemotherapy.2,3 To date 
there have been few studies examining this problem using multi-modality imaging techniques to 
better understand this complex and significant problem.  
 
FDG-PET and fMRI are routinely used in clinical practice for the evaluation of cognitive 
dysfunction in older populations complaining of memory dysfunction. It is well recognized that 

PI: Jeffrey Yap, PhD  
 
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Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
Version Date: 03/21/2024 
 
 
University of Utah IRB  
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FDG-PET can assist with the differentiation and characterization of various cognitive disorders 
due to unique patterns of cerebral metabolism caused by various cognitive and dementia-causing 
disorders.4-6 FDG-PET has been studied extensively in dementia research and has a high reliability 
in detecting Alzheimer’s disease (AD) many years before it can be diagnosed reliably using 
clinical criteria.4 
 
To our knowledge, there has been only a single small study using FDG-PET and bolus water 
activation paradigms in cancer patients complaining of memory problems.7 To date, there have 
been no studies using [18F]Flutemetamol as a PET imaging agent to assess the possibility of 
increased amyloid plaque burden as a potential contributing factor to the cognitive deficits and 
complaints seen in patients experiencing CICI. The novel feature of this project is in the combined 
use of [18F]Flutemetamol-PET, FDG-PET, and fMRI to study a poorly understood but common 
problem: cognitive impairment in breast cancer patients treated with chemotherapy. 
 
If [18F]Flutemetamol, FDG-PET, and fMRI can provide information on the pathophysiology of this 
disorder, it will be an important step in better understanding the etiology of this phenomenon and 
possibly other conditions resulting in cognitive dysfunction. These imaging assessments will make 
it possible to explore any altered changes in cerebral structure, metabolism, and amyloid 
deposition that may be responsible for CICI. This may help to predict which individuals may be 
affected by this problem and provide information for eventual therapeutic strategies to treat this 
common cancer-associated disorder.  
 
This study will use [18F]Flutemetamol and FDG-PET imaging to assess and quantify the amyloid 
plaque burden and cerebral glucose metabolism, respectively, in breast cancer patients suffering 
from CICI and correlate those findings with structural changes on MRI. The [18F]Flutemetamol 
and FDG-PET scans of these study patients will then be compared to two GE software databases 
(CortexID-FDG and CortexID-Flutemetamol) which contain scan data from healthy control 
individuals to evaluate for abnormalities in cerebral glucose metabolism and amyloid plaque 
burden differing from the values expected for individuals in their age range.   
 
2. BACKGROUND 
Currently, a woman living in the US has a 12.2%, or a 1 in 8, lifetime risk of being diagnosed with 
breast cancer and approximately 232,340 new cases of invasive breast cancer will be diagnosed 
among women in the United States this year.8 Presently, the overall 5-year relative survival rate for 
female breast cancer patients has improved from 63% in the early 1960s to 90% today, an increase 
due largely to improvements in treatment.9   
 
One such treatment is chemotherapy, a treatment that consists of drugs that are toxic to tumor cells 
or inhibit their growth through various pathways.10 The majority of women with breast cancer will 
receive adjuvant therapy including chemotherapy, hormone therapy, or both, which has shown to 
improve disease-free and overall survival.11 
 

PI: Jeffrey Yap, PhD  
 
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Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
Version Date: 03/21/2024 
 
 
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Although treatments such as chemotherapy have increased the overall survival rates of women 
with breast cancer, it is well known that chemotherapy treatment has numerous side effects, to 
include: nausea, diarrhea, fatigue, anemia, and other systemic side effects.12,13 These side effects 
compound the neuropsychological and quality of life effects of having a cancer diagnosis, a 
diagnosis that often affects individuals overall psychological wellbeing. Many people who undergo 
chemotherapy, particularly adjuvant chemotherapy, also complain of cognitive dysfunction.14,15  
 
This cognitive decline affects 16-50% of individuals receiving long-term adjuvant 
chemotherapy.2,3 Some reports suggest this figure may be even higher; Jenkins et al. reported that 
up to 83% of breast cancer survivors report some form of subjective cognitive dysfunction.16 
 
Most research claiming evidence for the existence of CICI has specifically investigated outcomes 
for women with breast cancer.17 These women often complain of inability to concentrate, memory 
dysfunction, word-finding difficulties, slowed processing abilities, and inability to multitask.17-28 
Similar to patients with CICI, individuals with Mild Cognitive Impairment (MCI) typically have 
cognitive deficits beyond expectations for normal aging, but do not yet demonstrate the severe 
functional impairments seen in AD.3,29  
 
Research suggests that one marker that might indicate the early development of AD is MCI, where 
MCI is a transitional phase between normal aging and dementia.29,30 MCI is most widely defined 
as having: (1) memory complaint; (2) impairment on a memory test after correction for age and 
education; (3) preserved general cognitive functioning; (4) intact activities of daily living; and (5) 
absence of dementia.31 Individuals with MCI progress to AD at much higher rates than their 
cognitively healthy peers (e.g., 10 – 15% vs. 1 – 2 % per year).29 
 
AD is the most common cause of progressive cognitive decline in the United States. Clinically, it 
is characterized by severe impairments in learning and memory and other cognitive abilities, which 
significantly interfere with daily functioning. The neuropathologic hallmarks of AD consist of 
neuritic plaques, neurofibrillary tangles, and selective neuronal cell loss.32 Neuritic plaques contain 
Amyloid-beta protein (Abeta) that forms amyloid deposits. Thus, Abeta is believed to play an 
integral role in the development of AD.33 Elevated levels of Abeta in the brain are correlated with 
cognitive decline,34 and removal of plaques in animal models of AD results in behavioral 
improvements.35 AD develops insidiously making it difficult to identify early; yet, treatment will 
be most effective when begun before neuronal loss is too extensive. Therefore, the search for 
markers of early AD, such as MCI, have received considerable interest. 
 
The current project will examine biomarkers that are consistent with MCI such as increased 
amyloid plaque burden and decreased cerebral glucose metabolism. For example, the first amyloid 
binding radioligand was 11C-PIB (Pittsburgh compound B) and initial studies found that amyloid 
burden assessed with 11C-PIB was high in patients with AD.36 Other work using 11C-PIB in 
patients with MCI has had mixed results, with some studies showing high amyloid burden,37-39 
while others have found low amyloid burden.40-42 However, the short half-life of 11C-PIB makes it 

PI: Jeffrey Yap, PhD  
 
     Page 9 of 73 
Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
Version Date: 03/21/2024 
 
 
University of Utah IRB  
Document Version:  010312 
challenging to work with in large clinical trials, so additional amyloid binding radio ligands have 
been developed.43 A longer half-life amyloid binding agent, [18F]Flutemetamol, shows promise in 
early AD and MCI.  
 
Other neuroimaging biomarkers of AD include FDG-PET and hippocampal volume on MRI. FDG-
PET measures metabolism of glucose in the brain. Patients with AD show a characteristic pattern 
of hypometabolism of bilateral temporal and parietal lobes on FDG-PET, which differentiates this 
condition from other causes of dementia.36 Hippocampal atrophy, as assessed by reduced volumes 
of these bilateral structures in the medial temporal lobes, has been shown in multiple studies to be 
an indicator of the development of AD.44 Limited work has been done using neuroimaging in CICI 
and MCI. This study will make an important contribution to the understanding of the earliest 
changes of cognition and the appropriate role of amyloid, FDG-PET, and MR imaging in breast 
cancer patients experiencing CICI. 
 
2.1 Review of Previous Research 
Current research suggests that the etiology of CICI is multi-factorial with many factors combing to 
predispose certain individuals to develop CICI45 A number of theories as to why chemobrain may 
occur have been proposed, including: neurotoxicity, oxidative stress, decreases in white and gray 
matter volume, and genetics; these have each been suggested to play a role in the development of 
chemobrain.19,46-49 
 
For many older women, the impact of chemotherapy may be compounded by the natural aging 
process, which, in and of itself, can be related to the development of cognitive problems.50,51 For 
younger women, the cognitive side effects related to chemotherapy may be compounded by the 
fact that chemotherapy can accelerate the onset of menopause.52 This is particularly important as 
menopause itself causes hormonal changes that can affect cognitive functioning.53 Other cancer 
treatments, including hormone therapy, immunotherapy, and radiation therapy have also been 
implicated as causing complaints of cognitive dysfunction.54 Findings indicated that CICI is a 
relatively common event that in most of the cases remains under diagnosed, thereby adversely 
affecting the quality of life of patients with cancer.55 
 
 
The following is a summary table (Table 1) of several published studies and the broad types of 
cognitive deficits that have been described.  
 
 
 
 
 
 
 

PI: Jeffrey Yap, PhD  
 
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Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
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Table 1. Types of Cognitive Deficits That Have Been Associated with Chemotherapy  
STUDY 
 
 
ATTENTION/ 
CONCENTRATION 
VERBAL 
MEMORY 
VISUAL 
MEMORY 
VISUAL/ 
SPATIAL 
SPEED OF 
INFORMATION 
PROCESSING 
Hodgson 
(2013)56 
 
 
 
 
++ 
 
Kesler 
(2013)57 
 
 
++ 
 
 
 
Bruno 
(2012)24 
 
 
++ 
 
 
 
Nokia 
(2012)22 
 
 
++ 
 
 
 
Meyers 
(2012)26 
 
++ 
++ 
 
 
 
Hedayati 
(2012)58 
 
++ 
++ 
 
 
++ 
Jim 
(2012)59 
 
 
++ 
++ 
 
 
Briones 
(2011)60 
 
 
++ 
 
 
 
Deprez 
(2012)61 
 
++ 
 
 
 
++ 
Von 
(2009)28 
 
 
++ 
 
 
 
Castellon 
(2004)62 
 
 
 
++ 
++ 
 
Ahles 
(2002)63 
 
 
++ 
 
 
++ 
Brezden 
(2000)64 
 
 
++ 
++ 
 
 
Schagen 
(1999)65 
 
++ 
++ 
++ 
 
++ 
van Dam 
(1998)66 
 
++ 
 
++ 
 
++ 
Wieneke 
and Dienst 
(1995)67 
 
++ 
++ 
++ 
++ 
++ 
 
NOTE. ++ indicates deficits noted in a particular study.  
 

PI: Jeffrey Yap, PhD  
 
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Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
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One of the largest obstacles in studying the impact of chemotherapy on cognitive is the difficulty 
in sorting out which problems are due to chemotherapy and which are due to having a serious 
illness like cancer.68  
 
There are multiple life stressors in this population that can result in physical debilitation, 
depression, sleep disruption, hormone shifts, and fatigue, all of which can affect cognitive 
functioning. Furthermore, a complex interplay may exist among cognitive function, psychological 
wellbeing, and quality of life. For example, a decrease in psychological wellbeing in the face of a 
poor health-related quality of life may have implications for cognitive function. Cognitive 
impairment that interferes with an individual’s daily routine may decrease that person’s 
psychological wellbeing. A number of studies investigating the effects of chemotherapy on health-
related quality of life and cognition have been published.69,70 
 
The Netherlands Cancer Institute group has published findings from a longitudinal study 
investigating the long-term effects of chemotherapy on cognition. The initial findings suggested a 
dose-response effect of chemotherapy on cognition, with cognitive impairment most pronounced 
in the high-dose group (32%) and least evident (9%) in the group receiving local treatment for 
breast cancer.66 Cognitive impairment in attention, mental flexibility, speed of information 
processing, visual memory, and motor function was observed in 28% of individuals 2 years after 
cyclophosphamide, methotrexate and fluorouracil (CMF) chemotherapy treatment.65 Self-reports 
of cognitive function were not related to cognitive function as measured by the neuropsychological 
tests, but instead were related to reports of anxiety and depression. In a two-year follow-up (4 
years post-treatment) the individuals who had received CMF showed improved cognitive 
performance and no longer scored significantly different than the controls.71 Although this group 
was the first to attempt a longitudinal study of chemotherapy and cognition, the study lacks a 
baseline measurement. 
 
This same group completed a prospective study that did include baseline measurements of 
cognitive function, and reported that a subset of patients receiving high dose cyclophosphamide, 
thiotepa, and carboplatin chemotherapy experienced a decline in objective cognitive performance 
and in particular in measurements of executive function.72 Such an effect was not observed in the 
standard-dose chemotherapy group, and it is not well understood whether these results generalize 
to other common high-dose chemotherapy regimens, such as dose dense doxorubicin (Adriamycin) 
and cyclophosphamide (cytoxan). 
 
Researchers from the M.D. Anderson Cancer Center were among the first to prospectively study 
cognitive function in relation to chemotherapy. Cognitive impairment was reported in 35% of 
patients73 and 33% of patients74 prior to the beginning of chemotherapy. Sixty-one percent of 
patients receiving a chemotherapy regimen of 5-fluorouracil, doxorubicin, and cyclophosphamide 
exhibited cognitive decline following chemotherapy treatment, primarily in areas of attention, 
learning, and processing speed.74 In the long-term follow-up, 50% of individuals who had shown a 
decline in cognitive function did not show improvement in the long-term. Although this study was 

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Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
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limited by a small sample size (n=18), it suggests that cognitive dysfunction occurs in a significant 
portion of individuals following chemotherapy. 
 
Iconomou and colleagues75 examined changes of emotional distress, cognitive impairment, and 
quality of life in a group of Greek cancer patients before treatment and at the end of treatment. 
Cognitive dysfunction was observed in 15% of the patients at baseline and was unchanged at the 
end of treatment. The lack of significant differences in this study may be attributable to the 
heterogeneity of the cancer diagnoses in the participants, as well as the use of the mini mental state 
exam (MMSE) as the sole objective measure of cognitive performance. 
 
A well designed prospective study by Jenkins16 using neuropsychological tests and self-reports of 
cognitive failures and quality of life found that although a decline in cognitive performance was 
more common in the group receiving chemotherapy compared to local treatment and healthy 
controls groups, no significant difference was seen immediately after chemotherapy or 18 months 
after the first assessment. One explanation for this finding may be that the majority of individuals 
received a relatively low dose of fluorouracil, epirubicin and cyclophosphamide, a treatment that 
had previously been shown not to increase an individual’s risk of cognitive impairment.66 
 
In one longitudinal study of cognition and breast cancer,76 Hermelink reported a decline in 
cognitive function in 27% of individuals at the end of chemotherapy relative to the beginning of 
treatment and an improvement in 28% of individuals receiving treatment. It is unlikely that 
chemotherapy improves cognitive function. This study may have had a flawed baseline measure or 
may have failed to take into account practice effects from multiple neuropsychological testing 
periods. 
 
In addition to the numerous studies of cognition in patients with cancer, there have also been 
several studies that have examined chemotherapy-treated animals. One of these trials showed that 
rats treated with cyclophosphamide and doxorubicin exhibited disruption of hippocampal 
neurogenesis.77 This anatomical change was associated with impaired performance on a novel 
place recognition task. Another such study using rats also demonstrated learning and memory 
impairment and decreased hippocampal cell proliferation following the administration of CMF.60   
These studies illustrate that chronic treatment with commonly used chemotherapeutic agents may 
act to impair cognitive ability through perturbation of neurogenesis in the hippocampus. 
  
There are a number of theories proposing different mechanisms to explain the development of 
CICI. One hypothesis is that some chemotherapy agents may cross the blood-brain barrier, directly 
causing neurotoxicity. However, others insist that most cytotoxic drugs are unable to cross the 
blood-brain barrier, and that the cognitive effects seen in patients with CICI are secondary to 
systemic inflammation brought on by the chemotherapy.78 Another theory states that the cognitive 
problems are due to free radicals produced by the chemotherapeutic agents.46 Others hypothesize 
the underlying genetic background makes some patients more susceptible to the effects of 

PI: Jeffrey Yap, PhD  
 
     Page 13 of 73 
Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
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chemotherapy. Finally, there is evidence of long-term injury to both white and gray matter in the 
brain following high-dose adjuvant chemotherapy.79  
 
The true etiology of CICI is most likely multifactorial with a combination of processes that 
together, predispose certain individuals to develop deficits in cognition. There is still much to be 
learned about this condition, including why it affects only a subset of patients and why these 
deficits can persist after completion of chemotherapy. It isn't clear which chemotherapy drugs are 
more likely to cause cognitive changes or if risk is proportional to dosage. There are currently no 
medications specifically approved to treat CICI, however, agents used to treat disorders such as 
depression, attention-deficit hyperactivity disorder and dementia have been investigated.80-87 
Cognitive-behavioral therapy has so far proved to be the most effective treatment to improve 
cognitive deficits and quality of life. 57,88-90 
 
Chemotherapy isn't the only cancer treatment that may cause cognitive disturbance and memory 
complaints. Other cancer treatments that have been implicated as causing complaints of cognitive 
dysfunction include hormone therapy, immunotherapy, and radiation therapy. Hormone therapy is 
common in woman being treated with conventional chemotherapy. It is not entirely clear if women 
undergoing hormone therapy, which alters the amount of systemic estrogen, experience memory 
problems.91 Some studies link memory to the amount of estrogen in the brain.92 Immunotherapy is 
typically an experimental therapy, which stimulates the immune system to fight cancer. Treatment 
with cytokines, a type of protein causes inflammation, which in turn may cause problems with 
memory, multitasking and difficulty with processing information.93 Radiation to the brain has been 
associated with cognitive, memory and motor function impairment. As with chemotherapy and 
immunotherapy, radiation therapy has also been associated with complaints of inability to learn 
and to multitask.94 Older adults and individuals receiving higher doses of radiation are at a greater 
risk of memory problems. It has been noted that individuals who receive both chemotherapy and 
radiation therapy to the brain have an increased risk for cognitive impairment.95  
 
2.2 NEUROPSYCH ASSESSMENTS FOR CICI 
Existing literature suggests that chemotherapy has adverse effects on memory, processing speed, 
and executive functioning.96 As such, we will focus our neuropsychological assessments on these 
three cognitive domains. To assess memory, we will utilize the Hopkins Verbal Learning Test – 
Revised (HVLT-R)97 and the Brief Visuospatial Memory Test – Revised (BVMT-R).98 Processing 
speed will be tapped with Trail Making Test Part A (TMT-A)99 and the Coding and Symbol Search 
subtests of the Wechsler Adult Intelligence Scale – IV.100 Executive functioning will be measured 
with Trail Making Test Part B (TMT-B),99 Controlled Oral Word Association Test (COWAT),101 
and Stroop Color Word Test (SCWT).102 Additionally, the Wide Range Achievement Test 
(WRAT4) will be used to assess premorbid intellect in all participants. Lastly, the Beck 
Depression Inventory – II (BDI-II)103 will be used to evaluate depressive symptoms, the Cognitive 
Failures Questionnaire (CFQ)104 will be used to determine subjective complaints of memory 

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difficulties, and the Frontal Systems Behavioral Scale will be used to determine subjective 
complaints of executive dysfunction. 
 
2.3 MRI IMAGING IN PATIENTS WITH CICI 
 
Brain volumetric imaging allows determination of cortical and subcortical atrophy associated with 
effects of chemotherapy, and should be targeted to identify both brain volume and cortical 
thickness. Brain volumetric imaging is an important covariate because it is one of the few 
noninvasive imaging metrics that is associated with dementia.44 We propose an MRI examination 
using high quality MPRAGE images to allow comparison with large multisite control populations 
such as the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database.105 
 
2.4 [18F]FLUTEMETAMOL as an IMAGING AGENT  
Biomarkers of AD recently have become extremely important to improve diagnosis, measure 
severity of disease, evaluate progression of disease, assess the effects of novel disease-modifying 
drugs, and to speed development of these novel experimental drugs by reducing the time needed to 
follow patients, the number of patients to be followed per study, and the cost of research.106,107  
 
AD neuropathology consists of neuritic plaques, neurofibrillary tangles, and neuronal cell loss.32 
Amyloid plaques are believed to play an integral role in the development of AD.33 Plaques are 
neurotoxic,108 and elevated levels of Abeta in the brain are correlated with cognitive decline.34 
Removal of plaques in animal models of AD has shown behavioral improvements.35 Several 
compounds with affinity for binding amyloid in vivo are under investigation.  These mainly fall 
into 3 families: a) naphthyls (e.g. [18F]FDDNP) which bind to plaques and tangles,109 thioflavins 
(e.g. PIB) which are selective for amyloid plaques,110 and c) stilbenes (e.g. 11C-SB13) which are 
similar to PIB, but have more background uptake variability.111  
 
“Pittsburgh Compound B” (11C-PIB), a radioactive carbon-11 labeled benzothiazole analog with 
the right kinetic affinities to image amyloid beta (Abeta) deposited in neuritic plaques.112,113  11C-
PIB has statistically significant increased retention in AD cortical areas, relative to controls 
(P<0.05),112 and lesser amounts in frontotemporal dementia.114 Recently 18F-39-F-6-OH-BTA1 
(18FGE067), a structural thioflavin analog of 11C-PIB has been tested in early phase trials. The 
market name for 18F-GE067 is Vizamyl ([18F]Flutemetamol). Preliminarily, this agent appears to 
behave very similar to 11C-PIB but has the advantage of the 120 minute half-life of 18F compared 
to 20 minutes for 11C, making the agent much more practical for research and clinical use.  
 
Nevertheless, much more research is needed to better understand the diagnostic capabilities of 
amyloid imaging agents.  For example, there are no uniformly accepted standards for 
distinguishing levels of [11C]PIB or [18F]Flutemetamol binding that should be considered normal.  
Individual laboratories are reporting widely varying prevalence of [11C]PIB binding in cognitively 

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normal elderly individuals.  This could be accounted for on the basis of scanner characteristics, 
reconstruction algorithms, subject selection, or modeling. PET studies with FDG and [11C]PIB 
provide different and complementary information.   
 
Although some investigators report close agreement between FDG and amyloid imaging, this is 
not at all uniformly true.114,115 In addition, there is not always a sufficient correlation between 
amyloid imaging and clinical diagnosis or between FDG-PET and clinical diagnosis. It is likely 
that discrepancies between FDG-PET and amyloid imaging and clinical diagnosis is due to 
diagnostic errors, but follow-up studies incorporating autopsies are needed. 114 
2.5 [18F]-FDG as an IMAGING AGENT  
FDG is a well-validated and important radiopharmaceutical for measuring glucose metabolism in 
the assessment, diagnosis, and staging of patients with cancer.116,117 Investigators at UCLA 
published the first preliminary study using FDG-PET imaging in chemobrain.7 The study included 
resting FDG-PET brain imaging as well as a blood flow study using [15O]H2O-PET. The study 
assessed regional brain metabolism and blood flow in 16 women who had adjuvant chemotherapy, 
8 women who had breast cancer but did not undergo chemotherapy, and 10 healthy women with no 
history of breast cancer or chemotherapy. Both groups of cancer survivors underwent resting FDG-
PET scans to assess brain metabolism and [15O] H2O-PET activation scans to assess cerebral blood 
flow during memory-related tasks. 
 
Women in the chemotherapy group had decreased glucose metabolism in the superior frontal gyrus 
and in Broca's area in the dominant hemisphere and in its contralateral counterpart, compared with 
the control group. Poor performance on measures of short-term recall correlated well with 
decreased metabolism in Broca's area in the chemotherapy group. In addition, women who had 
undergone chemotherapy had increases in blood flow that were strongest in the inferior frontal 
gyrus region (Broca's area), compared with women who did not undergo chemotherapy. The 
researchers also looked at differences in chemotherapy regimens. Women who received 
chemotherapy and tamoxifen had decreased resting metabolism in the lentiform nucleus. 
Activation patterns during a short-term recall task were abnormal in the same areas in these 
women. 
 
The UCLA study was not a quantitative study as is proposed here. This is important as there may 
be alterations in the transport of glucose and hexokinase activity secondary to chemotherapy and 
that can be assessed using dynamic and quantitative FDG-PET as we propose. Altered glucose 
transport has been seen in other dementing diseases.118 A complete search of the literature has 
shown there to be no other PET imaging studies assessing CICI in patients with solid organ 
cancers. However, two studies have been recently published showing alteration of cerebral glucose 
metabolism in Hodgkin’s119 and non-Hodgkin’s lymphoma.120 
 

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3. PHARMACOLOGY, METABOLISM, AND BIODISTRIBUTION OF 
[18F]FLUTEMETAMOL (as described in the [18F]Flutemetamol Investigator’s Brochure 
and Vizamyl Package Insert)1 
 
3.1 Pharmacology of [18F]Flutemetamol 
[18F]Flutemetamol Injection is a fluorine-18 labeled PET diagnostic agent supplied as a ready to 
inject solution. Vials for multi-dose use contain up to 10 ml of [18F]Flutemetamol. 
 
The drug substance is [18F]Flutemetamol; its structural representation is shown below. It is derived 
from the basic structure of the dye thioflavin-T. 
 
 
 
The formulation of [18F]Flutemetamol for injection (drug product) contains 7% ethanol (v/v), 0.9% 
sodium chloride (w/v) and 0.5% polysorbate 80 (w/v) in phosphate buffer (0.014 M). The pH of 
the drug product is 6.0-8.5. The radiochemical purity (RCP) is greater than 90% throughout shelf 
life. 
 
18F-Flutemetamol is manufactured by automated radiosynthesis followed by purification, 
formulation with buffer and aseptic dispensing. 
 
Physical properties of fluorine-18: 
Fluorine-18 decays by positron emission (+ decay, 96.7%) and orbital electron capture (3.3%) with 
a half-life of approximately 110 minutes. The positron undergoes annihilation with an electron to 
produce two gamma photons each of energy 511 keV (193.4% emission). 
 
3.2 Dosage form 
[18F]Flutemetamol for injection is a sterile, aqueous solution of [18F]Flutemetamol and excipients 
for intravenous administration. The product is supplied with a radioactive content of 150 MBq/ml 
(4.05 mCi/ml) at the reference date and time as specified on the label in a glass vial sealed with a 
synthetic rubber closure and aluminum overseal or a unit dose syringe. The patient dose will 
normally be transported from the manufacturing site in syringes or vial. However, the patient dose 
may be transported in its original container and withdrawn into syringes at the clinical site. Each 
vial or syringe is transported in lead or tungsten shielding. Each patient dose will contain up to 185 
MBq (5 mCi) ±10% at the time of administration and not more than 6.0 µg/ml [18F]Flutemetamol 
(non-radioactive analogue of the drug substance). The radioactive dose will be measured in a dose 

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calibrator before administration. The maximum administered dose volume is approximately 10 ml. 
The product must not be diluted. 
Equipment typically used to administer the drug product should be one or more items from the 
following list. 
• 
Needle 
• 
Syringe  
• 
Catheter  
• 
Stopcock  
• 
Infusion line  
 
Quality control of the drug product: 
The quality control (QC) analysis of a sample of the drug product may be performed in parallel 
with transportation of the drug product to the imaging suite. The investigator (or nominated 
deputy) will receive release/reject information for the drug product. Only product for which 
confirmation of release has been received shall be used. 
 
Storage and handling: 
The in-use shelf life of [18F]Flutemetamol for injection is up to 10 hours from the end of 
production and the product must not be used beyond this limit. The shelf life may be extended as 
additional stability results become available. [18F]Flutemetamol should be stored at 2-30°C (36-
86°F) in a shielded container.  However, temperature excursions up to 50°C (122°F) during 
transport are acceptable. Waste must be disposed of according to national regulations for 
radioactive material. 
Precautions for the safe handling of radioactive materials should be observed. 
 
3.3 In vitro Metabolism and Plasma Protein Binding of [18F]Flutemetamol 
Studies were performed to investigate the in vitro metabolism of [18F]Flutemetamol by incubation 
with hepatic S9 fraction obtained from man, dog, mouse and rat (where the rats had either been not 
treated or pre-treated with Aroclor 1254, a potent inducer of liver metabolizing enzymes). 
The major metabolite in these studies, irrespective of the origin of the hepatic S9, was the 
N-demethylation product of [18F]Flutemetamol. This is a preliminary indication that metabolism in 
the human primate is similar to that of the rat and dog, and gives support for these two species 
being appropriate for non-clinical studies. No metabolism or degradation was observed following 
incubation of [14C]Flutemetamol with citrated rat, dog or human plasma for up to 3 hours. Low 
levels of 2 metabolites were seen in citrated human whole blood at 3 hours. The binding of 
[3H]Flutemetamol to human, dog and rat plasma proteins was shown to be greater than 95% by 
equilibrium dialysis. Despite this high protein binding, [18F]Flutemetamol is rapidly eliminated 
from blood after intravenous administration of [18F]Flutemetamol to male and female Wistar rats. 
 

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3.4 In vivo Metabolism of [18F]Flutemetamol 
Data indicate that [18F]Flutemetamol is rapidly metabolized in rat, baboon and humans resulting in 
at least 2 radioactive hydrophilic metabolites. HPLC profiles of 11C labeled products present in rat 
and baboon plasma after intravenous administration of [11C]Flutemetamol were studied. In both rat 
and baboon, [11C]Flutemetamol was rapidly metabolized and at least 2 hydrophilic products were 
observed and the retention times of these hydrophilic products were comparable in both rat and 
baboon plasma. After injection of [18F]Flutemetamol in the Phase I study human plasma samples 
from the subjects were analyzed by HPLC. These samples were primarily taken to assist with brain 
kinetic modeling but they also showed that metabolism of the injected [18F]Flutemetamol occurred 
rapidly (only 25% of the parent compound detected in the circulation 20 minutes post injection and 
approximately 10% detected in the circulation at 180 minutes post injection) and at least 2 
hydrophilic metabolites were detected. 
Solubility and Stability: 
The maximum concentrations of [18F]Flutemetamol achievable in dosing solutions for the in vitro 
and in vivo studies were limited by the solubility of [18F]Flutemetamol in the appropriate vehicle 
for each test (e.g. phosphate buffered saline containing 7% (v/v) ethanol, and dimethylformamide 
(DMF)). Although polysorbate 80 (0.5% w/v) is now included in the clinical preparation, at the 
time the toxicology studies were carried out, it was not expected to be part of the clinical 
formulation and was not included in the preclinical Test Item. Subsequently, the risk of including 
polysorbate 80 (0.5% w/v) in the clinical formulation and administering it to humans has been 
assessed and is considered extremely low since it is a component of many approved intravenous 
preparations. 
 
4. TOXICITY and SAFETY OF FLUTEMETAMOL (as described in the [18F]Flutemetamol  
Investigator’s Brochure and Vizamyl Package Insert)1 
 
4.1 Flutemetamol Toxicology 
A complete toxicology package is part of the GE Healthcare IND # 101,866 which we have been 
allowed to cross reference. In brief, Single dose; 7-day and 14-day repeated intravenous dose GLP 
(Good Laboratory Practice) compliant toxicology studies have been conducted using Flutemetamol 
Solution for Injection in 2 mammalian species (rat and dog). For genetic toxicology assessment, 2 
in vitro cell assays; a bacterial reverse mutation test (Ames test) and a mouse lymphoma assay 
(MLA test), and 2 in vivo mammalian tests, a rat bone marrow micronucleus assay (MN), and rat 
liver unscheduled DNA synthesis (UDS) have also been conducted. Having obtained data in the in 
vitro systems that suggested potential mutagenicity, an additional bone marrow MN assay was 
carried out as part of a subsequent 14 day repeat dose study in rat. Local tolerance and irritation 
studies were performed to investigate whether Flutemetamol solution for injection induced signs of 
intolerance by dermal, ocular (conjunctival sac), intra-arterial, intramuscular, perivenous or 
intravenous route in rabbits. A further study to assess potential hemolytic effects of the vehicle on 
red blood cells was also carried out since the vehicle is known to have low osmolarity.  
 

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The complete pharm/tox package includes the following studies:  
• Expanded Acute Dose Toxicity Study in Rats 
• 7-Day Dose Range Finding Study in Rats 
• Combined Single Dose and 7-day Dose Range Finding Study in Dogs 
• 14-Day Repeated Dose Toxicity Study in Rats 
• 14-Day Repeated Dose Toxicity Study in Dogs 
• Microbial Mutagenesis Test (Ames) study 
• Mutation at the Thymidine Kinase (tk) Locus of Mouse Lymphoma L5178Y Cells using the 
Microtitre Fluctuation Technique (MLA) 
• Acute Rat Bone Marrow Micronucleus Assay (MN) 
• 14-Day Repeat Dose Rat Micronucleus Assay 
•  Measurement of Unscheduled DNA Synthesis (UDS) in Rat Liver using an in vivo/in vitro 
Procedure 
• Genotoxicity study, Reproductive Toxicity analysis, Local Tolerance in Albino Rabbits 
•  Primary Skin Irritation Study in Rabbits (4-Hour Semi-Occlusive Application) 
• Acute Eye Irritation/Corrosion in Albino Rabbits,  
• Osmolality and the Lack of Potential to Induce Haemolysis, B067061. 
 
4.2 Previous Human Studies with [18F]Flutemetamol   
The below table (Table 2) lists the recently published studies using [18F]Flutemetamol. 
 
Table 2. Current Published Studies Using Flutemetamol 
Koole 
(2009)121 
Koole M, Lewis DM, Buckley et al. Whole-Body Biodistribution and 
Radiation Dosimetry of 18F-GE067: A Radioligand for In Vivo Brain 
Amyloid Imaging. J Nucl Med 2009; 50:818–822. 
Nelissen 
(2009)122 
Nelissen N, Van Laere K, Thurfjell L et al. Phase 1 study of the Pittsburgh 
compound B derivative 18F-flutemetamol in healthy volunteers and patients 
with probable Alzheimer disease. J Nucl Med. 2009;50(8):1251-9. 
Vandenberghe 
(2010)123 
Vandenberghe, R, Van Laere, K, Ivanoiu, A et al. 18F-flutemetamol amyloid 
imaging in Alzheimer disease and mild cognitive impairment: A phase 2 trial. 
Annals of Neurology. 2010; 68(3):319-329. 
Wolk 
(2011)124 
 
Wolk DA, Grachev ID, Buckley C, et al. Association between in vivo fluorine 
18-labeled flutemetamol amyloid positron emission tomography imaging and 
in vivo cerebral cortical histopathology. Archives of neurology. Nov 
2011;68(11):1398-1403. 
Rinne 
(2012)125 
Rinne JO, Wong DF, Wolk DA, et al. [(18)F]Flutemetamol PET imaging and 
cortical biopsy histopathology for fibrillar amyloid beta detection in living 
subjects with normal pressure hydrocephalus: pooled analysis of four studies. 
Acta neuropathologica. Dec 2012;124(6):833-845. 

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Thurfjell 
(2012)126 
Thurfjell L, Lotjonen J, Lundqvist R, et al. Combination of biomarkers: PET 
[18F]flutemetamol imaging and structural MRI in dementia and mild cognitive 
impairment. Neuro-degenerative diseases. 2012;10(1-4):246-249. 
Adamczuk 
(2013)127 
Adamczuk K, De Weer AS, Nelissen N, et al. Polymorphism of brain derived 
neurotrophic factor influences beta amyloid load in cognitively intact 
apolipoprotein E epsilon4 carriers. NeuroImage. Clinical. 2013;2:512-520. 
Duara 
(2013)128 
Duara R, Loewenstein DA, Shen Q, et al. Amyloid positron emission 
tomography with (18)F-flutemetamol and structural magnetic resonance 
imaging in the classification of mild cognitive impairment and Alzheimer's 
disease. Alzheimer's & dementia: the journal of the Alzheimer's Association. 
May 2013;9(3):295-301. 
Duff 
(2013)129 
Duff K, Foster NL, Dennett K, et al. Amyloid deposition and cognition in 
older adults: the effects of premorbid intellect. Archives of clinical 
neuropsychology : the official journal of the National Academy of 
Neuropsychologists. Nov 2013;28(7):665-671. 
Leinonen 
(2013)130 
Leinonen V, Rinne JO, Virtanen KA, et al. Positron emission tomography 
with [18F]flutemetamol and [11C]PiB for in vivo detection of cerebral cortical 
amyloid in normal pressure hydrocephalus patients. European journal of 
neurology : the official journal of the European Federation of Neurological 
Societies. Jul 2013;20(7):1043-1052. 
Rinne 
(2013)131 
Rinne JO, Frantzen J, Leinonen V, et al. Prospective Flutemetamol Positron 
Emission Tomography and Histopathology in Normal Pressure 
Hydrocephalus. Neuro-degenerative diseases. Nov 27 2013. 
Wong 
(2013)132 
Wong DF, Moghekar AR, Rigamonti D, et al. An in vivo evaluation of 
cerebral cortical amyloid with [18F]flutemetamol using positron emission 
tomography compared with parietal biopsy samples in living normal pressure 
hydrocephalus patients. Molecular imaging and biology : MIB : the official 
publication of the Academy of Molecular Imaging. Apr 2013;15(2):230-237. 
Hatashita 
(2014)133 
Hatashita S, Yamasaki H, Suzuki Y, Tanaka K, Wakebe D, Hayakawa H. 
[(18)F]Flutemetamol amyloid-beta PET imaging compared with [(11)C]PIB 
across the spectrum of Alzheimer's disease. European journal of nuclear 
medicine and molecular imaging. Feb 2014;41(2):290-300. 
Thurfjell 
(2014)134  
Thurfjell L, Lilja J, Lundqvist R, et. al. Automated quantification of 18F-
flutemetamol PET activity for categorizing scans  as negative or positive for 
brain amyloid: concordance with visual image reads. J Nucl Med. 
2014;55(10):1623-1628 
 
 
In addition, the GE Healthcare Investigator’s Drug Brochure which is part of GE Healthcare IND # 
101,866 and subsequent amendments which we are allowed to cross reference (see cross reference 
letter) contains additional previous human experience which is summarized below.  
 

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Three clinical trials have been conducted to assess the effects in humans. In the first 2 clinical 
trials [11C]Flutemetamol ([11C]AH110690) was used. These are summarized in the GE Healthcare 
IND 101,866 as clinical trials ALZ101 and ALZ102. In the last clinical trial [18F] Flutemetamol 
([18F]AH110691) was used. This is known as trial ALZ103 with results being published in 2009.122  
 
4.2.1 ALZ101 Study 
A Phase 1, Proof of Concept Study to Evaluate the Uptake of [11C]AH110690 and 
[18F]AH110691 in the Brain of Healthy Volunteers and Subjects with Probable Alzheimer's 
Disease 
The study was conducted at 1 center in Turku, Finland, in the period September 2004 to 
February 2005. The primary objective of the study was to establish proof of concept and select the 
preferred candidate for entry into early development by comparing brain uptake of 2 agents, 
[11C]Flutemetamol and [18F]AH110691. Each of the agents were given as a single intravenous 
dose containing approximately 5 μg of drug substance and a radioactivity dose of maximum550 
MBq or maximum 382 MBq, respectively, by rapid bolus intravenous injection (less than 40 
seconds). In addition to the drug substance, the [11C]Flutemetamol injection contained 12% 
propylene glycol, 7% ethanol and phosphate buffer. 
 
In this study [11C]Flutemetamol was administered to 3 young healthy volunteers (HV; 30 years and 
younger), 10 older HV (from 50 to 85 years of age) and 10 probable AD cases (based on 
established criteria). Seventeen of these 23 subjects (3 young HV, 6 subjects with probable AD and 
8 older HV) received [18F]AH110691. 
 
Visual assessment of the positron emission tomography (PET) images was performed and uptake 
ratios (URs; both standard uptake values [SUV] and distribution volume ratios [DVR]) were 
calculated from pre-specified regions of the brain in all subjects. These URs were compared 
between subjects with probable AD and young HV and between subjects with probable AD and 
older HV. 
 
Efficacy Results of the ALZ101 Study 
[11C]Flutemetamol was able to differentiate between subjects with probable AD and HV on the 
basis of differences in regional and specific brain amyloid binding patterns. These differences were 
detectable visually and when using URs derived both from SUVs and DVRs relative to the 
cerebellum (i.e., the reference region). 
 
Evaluation of [11C]Flutemetamol scans using SUVs: In the frontal cortex, parietal cortex, occipital 
cortex, striatum, anterior cingular cortex and posterior cingular cortex, there was a tendency for 
higher URs with [11C]Flutemetamol in the subjects with probable AD than in the older HV. Brain 
areas with the most significant difference in [11C]Flutemetamol uptake between subjects with 
probable AD and HV were the frontal, parietal, anterior and posterior cingular cortices. 
 

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Evaluation of [11C]Flutemetamol scans using DVRs: In all examined areas of the brain except the 
medial temporal cortex, subcortical white matter and pons, there was a tendency for higher DVRs 
with [11C]Flutemetamol in the subjects with probable AD than in the older HV. Brain areas with 
the most significant difference in [11C]Flutemetamol uptake between subjects with probable AD 
and HV were the frontal, parietal, anterior and posterior cingular cortices. The higher URs and 
DVRs noted with [11C]Flutemetamol in these areas in subjects with probable AD suggested that 
[11C]Flutemetamol could be used to differentiate between healthy subjects and subjects with 
probable AD. 
 
When comparing [11C]Flutemetamol URs or DVRs in subjects with probable AD and older HV, 
significant test results were obtained in the frontal cortex (left and right), parietal cortex (left), 
anterior cingular cortex (left and right) and posterior cingular cortex (left and right [DVR only]). 
The higher URs and DVRs noted with [11C]Flutemetamol in these brain areas in subjects with 
probable AD suggested that [11C]Flutemetamol could have potential utility in diagnosing AD. 
 
The SUV and DVR analyses yielded comparable results suggesting that either or both methods can 
be used for future studies. In all examined areas of the brain, the URs with [18F]AH110691 were 
similar in the subjects with probable AD, young HV and older HV. Therefore, [18F]AH110691 was 
not able to differentiate between subjects with probable AD and HV using URs or DVRs. 
 
Safety Results of the ALZ101 Study 
Three subjects (13%) experienced a total of 4 adverse events (AEs). Two of 10 subjects with 
probable AD (20%) experienced 3 AEs and 1 older HV (10%) experienced 1 AE. The 3 young HV 
did not experience any AEs. Three AEs were of mild intensity and 1 AE was of moderate intensity. 
All AEs resolved during the study. None of the AEs were considered related to the investigational 
medicinal products (IMP). No SAEs or deaths were reported and no subjects were withdrawn due 
to AEs. 
 
Of the 23 subjects who received [11C]Flutemetamol or [11C]Flutemetamol and [18F]AH110691, 2 
subjects (9%) experienced AEs within the MedDRA body system of ‘nervous system disorders’. 
No other body system was evidenced in more than 1 subject. The most frequent AE was 
‘headache’ (2 subjects). The remaining 2 AEs, which occurred in 1 subject each, were ‘injection 
site extravasation’ and ‘vomiting’. The ‘injection site extravasation’ AE was actually a procedural 
complication with the arterial line used to take arterial blood samples and is not related to the drug 
product. 
 
Two AEs required action to be taken. One subject had the arterial line removed due to injection 
site extravasation’ and 1 subject was given medication for a headache. Examination of the 
occurrence of AEs, their intensities, and relationship to [11C-] Flutemetamol and/or 
[18F]AH110691 across the subject groups revealed no safety signal. 
 

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Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
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Based on the number and nature of the AEs and the fact that no SAEs occurred, the results of The 
ALZ101study indicate [11C]Flutemetamol to be safe and well tolerated. There was no specific 
profile for occurring AEs. The few AEs reported were primarily mild in intensity, resolved during 
the study, were deemed to be unrelated to [11C]Flutemetamol and did not result in withdrawals. 
Assessment of laboratory parameters for hematology, serum biochemistry and urinalyses, as well 
as vital signs and ECGs revealed no trends or other signals that were indicative of a safety concern. 
 
4.2.2 ALZ102 Study 
A Phase 1, 1-Year Follow-Up Study to Evaluate the Uptake of [11C]AH110690 in the Brain of 
Healthy Volunteers and Subjects with Probable Alzheimer’s Disease who Participated in Study 
ALZ101 
This study was conducted at 1 clinical site in Turku, Finland, in the period November 2005 to 
March 2006. 
 
ALZ102 was a clinical and PET imaging follow-up study to the ALZ101 study designed to further 
demonstrate the utility of the PET tracer [11C]Flutemetamol for imaging the amyloid burden and 
its changes over time in the brain of subjects with probable AD and HV. The areas of the brain 
where uptake was quantified comprised the frontal, medial temporal (hippocampus and amygdala), 
parietal, and occipital cortices, striatum, anterior and posterior cingular cortex, cerebellum, and 
white matter (subcortical and pons). 
 
In this study [11C]Flutemetamol was administered to 10 HV and 9 subjects with probable AD. The 
subjects were at least 50 years old and had already participated in study ALZ101. Nineteen 
subjects were dosed and evaluable for the safety analysis, and 18 subjects were evaluable for the 
efficacy analysis. One HV was excluded from the statistical analysis as he had developed an 
abnormal cognitive profile (mini-mental state examination [MMSE <27]) since Study ALX101. 
PET scanning commenced shortly before [11C]Flutemetamol injection and continued for 90 
minutes. Each subject received a single intravenous dose of [11C]Flutemetamol (approximately 5 
μg and less than 10 μg) by rapid bolus intravenous injection (less than 40 seconds). The activity of 
[11C]Flutemetamol did not exceed 550 MBq as already established in study ALZ101. The 
formulation of the IMP was the same as in ALZ101. 
 
Efficacy Results of the ALZ102 Study 
In this study, [11C]Flutemetamol imaging of the brain showed the potential to differentiate  
between subjects with probable AD and HV, both visually and using URs (derived from SUVs) 
and DVRs. In frontal, left parietal and the anterior and posterior cingular cortices there was a 
significantly higher UR in subjects with probable AD than HV. In the same areas of the brain, plus 
the left occipital cortex, there was a significantly higher DVR in subjects with probable AD than 
HV. 
 

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Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
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In the frontal, anterior and posterior cortices, 5 out of 9 subjects with a clinical diagnosis of AD 
had elevated DVRs, whereas 4 of the AD subjects had similar DVRs to those seen in HV. This 
pattern was consistent with that described in post-mortem studies of amyloid deposition in AD 
brain showing, from early stages of the disease process, amyloid plaque deposition distributed 
fairly evenly across neocortical association cortices whereas medial temporal lobe areas show 
relatively low amyloid burden. In terms of uptake distribution, ALZ102 results are in keeping with 
previous [11C]PIB studies135 and with the ALZ101 study results previously reported with 
[11C]Flutemetamol. 
 
Quantitatively, the ALZ102 study showed a 1.42 fold increase for [11C]Flutemetamol uptake 
(DVR) in frontal cortex of AD subjects (mean DVR 1.560.41) compared to normal subjects 
(mean DVR 1.100.15). Other cortical areas showed a lower DVR increase. In HV, [11C] 
Flutemetamol retention in the pons and subcortical white matter was greater than in cortical areas 
and very similar to the uptake values found in the pons and subcortical white matter of AD 
subjects. In AD subjects, retention in pons and white matter was greater than in association cortical 
areas. This suggests a higher non-specific retention of [11C]Flutemetamol in white matter than in 
grey matter areas. 
 
When compared with the ALZ101 study results, no significant changes in [11C]Flutemetamol brain 
uptake were observed in AD subjects or HV over the 1-year follow-up. In conclusion, this study 
showed that [11C]Flutemetamol brain retention provided a quantifiable discrimination between AD 
subjects and HV. Both URs and DVRs showed similar results in this study suggesting both 
methods of analysis are suitable for future use. The brain regions with the highest potential for the 
diagnosis of AD using [11C]Flutemetamol were the frontal, parietal, left and right anterior and 
posterior cingular cortices. 
 
Safety Results of the ALZ102 Study 
All 19 subjects (10 HV and 9 subjects with probable AD) receiving [11C]Flutemetamol were 
evaluable for safety. All subjects’ safety was monitored continuously during the course of the 
study and as part of a 24-hour telephone safety follow-up. ECG was monitored continuously from 
before injection to 15 minutes after injection (Lead II ECG). Vital signs (including 12-lead ECG) 
were monitored at 0.5 and 1.5 hours after injection and the injection site was monitored from 
before injection to 1.5 hours after injection. AEs were monitored continuously following injection. 
 
No AEs were experienced by HV subjects. Of the 9 subjects with probable AD, 2 subjects (22%) 
experienced 3 AEs (extrasystoles and 2 events of electrocardiogram QT prolongation). All of these 
events were mild in intensity and were considered not to be related to [11C] Flutemetamol. No AEs 
required action to be taken and all events resolved. No SAEs or deaths were reported and no 
subjects were withdrawn due to AEs. 
 
An examination of the occurrence of AEs, their intensities, and relationship to [11C]Flutemetamol 
across the subject groups revealed no safety signal. There were no individual clinically significant 

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Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
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laboratory abnormalities that were considered related to administration of [11C]Flutemetamol or 
indicative of a significant trend or safety signal. No laboratory abnormality resulted in a change in 
subject management or was reported as an AE. Systolic and diastolic blood pressure, heart rate, 
body temperature, respiratory rate and oxygen saturation measurements for all subjects were 
generally within the normal ranges and showed overall stability comparing baseline to post-
baseline measurements. The number of subjects who experienced changes greater than the 
specified magnitude for these parameters were attributed to normal variations expected in this 
population. No significant trends indicative of a safety concern were apparent. 
 
All ECGs from this study were read by an independent cardiologist. The following ECG intervals 
were measured in ms: PR, QRS, RR, and QTc using Bazett’s (QTcB) and Fridericia’s (QTcF) 
correction methods. Each QT value from this study was the maximum QT value among the 12 
leads in a given ECG, corrected as indicated for heart rate. QTc interval changes were assessed 
with reference to the levels suggested by the Committee for Medicinal Products for Human Use 
(CHMP). The CHMP categories suggest QTc interval prolongations of 30 to 60 ms as of potential 
clinical concern and prolongations 60 ms as of significant clinical concern. The number of subjects 
with absolute QTc intervals 440 ms was also assessed. 
 
A further exploratory analysis of QTc interval prolongation using a 20 ms prolongation\ threshold 
was performed. The maximum mean increase from baseline for QTc was 9 ms in subjects with 
probable AD and 11 ms in HV using Bazett’s correction method (occurring 1.5 hours after 
injection) and 11 ms in subjects with probable AD and 12 ms in HV using Fridericia’s correction 
method (occurring 30 minutes after injection). The frequency of subjects with QT interval values 
>440 ms were similar, irrespective of the correction method used; 5 subjects using Bazett’s and 
Fridericia’s correction (2 subjects with probable AD and 3 HV) had at least 1 QTc value >440 ms. 
Three of the 5 subjects who had post-injection QTc >440 ms also had at least 1 pre-injection QTc 
measurement >440 ms for both the Bazett’s and Fridericia’s corrections. Therefore, only 2 subjects 
showed de novo QTc measurements >440 ms post-injection. Only 1 subject demonstrated a 45 ms 
post-baseline increase (HV, increase in Bazett’s QTc of 48 ms at 24 hours post-dose) in QTc 
interval using either correction method. The number of subjects with QTc interval prolongation 30 
ms was low, 4 subjects, using Bazett’s correction method and 1 subject using Fridericia’s 
correction method. The frequency of subjects with QTc interval prolongation 30 ms was higher 
using Bazett’s correction (4 subjects) compared to Fridericia’s correction (1 subject). A review of 
changes in QTc interval 20 ms changes across all time points showed no cause for clinical concern 
when data was examined using both correction methods. There was no evidence for a temporal 
relationship to IMP. 
 
In total, 7 dosed subjects demonstrated a 20 ms post-baseline increase in QTc interval using 
Bazett’s correction method and 11 subjects using Fridericia’s correction method. These changes 
were attributable to normal daily variability in this study population. 
 

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Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
Version Date: 03/21/2024 
 
 
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In conclusion, although QTc interval prolongation 30 ms was observed in 4 subjects, extensive 
review of the data showed no findings of clinical concern. There were no individual clinically 
significant ECG abnormalities following administration of [11C]Flutemetamol indicative of a 
significant trend or safety signal. In this study of 19 subjects who were dosed with 
[11C]Flutemetamol and who had ECG data recorded, no evidence was found that administration of 
[11C]Flutemetamol led to clinically relevant changes in ECG intervals or waveforms. 
 
4.2.3 ALZ103 Study 
A Phase 1, Open-label Study to Assess Safety, Biodistribution, and Radiation Dosimetry and to 
optimize the Imaging Protocol of [18F]AH110690 Injection in Healthy Volunteers and Subjects 
with Probable Alzheimer’s Disease121,122 
This study was conducted at 1 center in Leuven, Belgium in the period October 2007 to March 
2008. In this study [18F]Flutemetamol was used for the first time. [18F]Flutemetamol is a PIB 
benzothiazole derivative radiolabelled with 18F with the potential as a diagnostic biomarker for 
beta amyloid deposition in human. 18F labeling was chosen rather than 11C because of the longer 
half-life. 18F has a half-life of approximately 109 minutes while 11C half-life is only 20.4 min.  
This was a phase 1, single center, single dose, open-label, non-randomized study to evaluate the 
safety, biodistribution, and radiation dosimetry and to optimize the imaging procedure of 
[18F]Flutemetamol injection in HV and subjects with probable AD. Twenty-two evaluable subjects 
– 8 subjects with a diagnosis of probable AD and 14 HV – aged 50 years or older were included in 
the study. The presence of probable AD and/or the lack of dementia (i.e., HV) were verified by 
comprehensive cognitive/neuropsychological examinations.  
 
The study consisted of a minimum of 2 visits for each subject. Each subject attended a screening 
visit within 30 days before injection of the IMP, i.e., [18F]Flutemetamol injection. During the 
screening visit the subjects had to satisfy all entry criteria and undergo safety assessments. On the 
day of PET imaging, each subject received a single dose of [18F]Flutemetamol by bolus IV 
injection. A computed tomography (CT) scan (i.e., CT attenuation correction scan) was performed 
prior to the initial PET scan and then repeated as required prior to any subsequent scan following 
an out of scanner break and repositioning. All subjects’ safety was monitored continuously during 
the course of the study and as part of a 24-hour telephone safety follow-up. Enrollment into the 
study proceeded in a 3-step fashion. The structure of the specific visits varied depending upon the 
step into which the subject was enrolled. 
 
Step 1 consisted of the evaluation of biodistribution, internal radiation dosimetry, ED, interim 
safety and an analysis of the % content of radioactive parent (active ingredient) and any of its 
derivative metabolites present in 6 HV. Subjects within this group underwent a whole body PET 
scan. Time-activity curves were generated and integrated to obtain the cumulated activity in each 
source organ or region which was then used to determine the internal radiation dosimetry using the 
Medical Internal Radiation Dosimetry (MIRD) schema.  
 

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Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
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In order to ensure individual subject safety, the decision to proceed to dosing additional subjects 
was made after an interim review of safety and internal radiation dosimetry data had been 
conducted on the first 2 evaluable subjects who received an injected activity of 100 MBq. The 
dosing of the remaining 4 subjects in Step 1 was then revised to 150 MBq. A 2nd review of safety 
and internal radiation dosimetry data was conducted once all 6 evaluable subjects had been 
completed. 
 
No safety concerns were raised after injection of [18F]Flutemetamol in the 6 HV in Step 1, and 
Step 2 was initiated with the recruitment of 3 subjects with a diagnosis of probable AD and 3 
additional HV. Interim efficacy/safety data and kinetic modeling of the brain distribution of 
[18F]Flutemetamol was performed in this population. Dynamic PET scans with 185 MBq 
[18F]Flutemetamol were acquired and volume of interest (VOI) analysis carried out for each 
subject. Time-activity curves of the brain were generated to compare the time-dependent 
distribution of the IMP in the brain of subjects with probable AD and HV. This comparison was 
expected to help in defining the best model for representing the kinetics of tracer uptake.  
 
Just prior to IMP administration an arterial line was established and maintained throughout the 
duration of the scanning period in each subject. Arterial blood samples were taken to derive safety 
measurements and 18F-activity measurements. Arterial and venous blood samples were taken to 
perform an analysis of the % content of radioactive parent and any radiolabelled derivative 
compounds present.  
 
Dynamic imaging coupled with arterial sampling provided additional information on the imaging 
characteristics of the brain. Data generated during this step of the protocol was used to refine the 
optimal imaging window used in Step 3. For Step 2 and Step 3, brain magnetic resonance imaging 
(MRI) scans were performed during the screening period (before PET scanning) with the images 
used to rule out cerebro-vascular, structural disorders and to assist production of a template for 
VOI analysis of the PET tracer uptake. 
 
No safety concerns were raised following an analysis of the data from Step 2, and enrolment into 
Step 3 was initiated. This final step consisted of imaging optimization and additional safety and 
efficacy assessments. Five additional subjects with a diagnosis of probable AD and 5 additional 
HV were recruited. A single dynamic PET scan was acquired after injection of 185 MBq 
[18F]Flutemetamol and VOI analysis carried out for each subject. However, the specific start time 
point after tracer administration was influenced by the results obtained from Step 2. Time-activity 
curves of the brain were generated to compare the time-dependent distribution of the IMP in the 
brain of HV and subjects with probable AD. This comparison was expected to help in defining the 
optimal time from injection to start of acquisition as well as the minimum injected activity and 
duration of acquisition. 
 
Efficacy Results of the ALZ103 Study 

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Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
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Efficacy from Step 2 and Step 3: URs were calculated and compared for [18F]Flutemetamol in HV 
and subjects with probable AD. In all examined areas of the brain except the pons, there was a 
tendency for higher URs with [18F]Flutemetamol in the subjects with probable AD than in the HV. 
Statistical analysis (Wilcoxon-Mann-Whitney test) to compare URs in subjects with probable AD 
and HV showed that significant test results were obtained for all cortical brain areas, except the 
anterior cingular cortex for the 85-minute scan start time. Therefore, [18F]Flutemetamol was able 
to differentiate between subjects with probable AD and HV using URs. A visual assessment 
showed that 2 AD subjects had images similar to the HV images and 1 HV had images similar to 
the AD images. Calcification of the brain was detected in Step 3 in AD subject 017 and was 
classified by the Principal Investigator (PI) as an incidental finding with no clinical significance. 
The PI reassured that this subject fulfilled all entrance and exclusion criteria. The impact of 
different scanning windows on the discrimination between subjects with probable AD and HV was 
analyzed using the Wilcoxon statistical test. 
 
Analysis of the results showed that different scan lengths (5 to 40 minutes) had a negligible effect 
on discrimination. The same analysis of the effect of different start times post-injection of IMP 
also showed a very small difference, but with a minor improvement in discrimination for later scan 
start times. Dosimetry estimates in Step 1 HV determined that the injected activity for subsequent 
studies using [18F]Flutemetamol could be increased to 185 MBq, corresponding to an effective 
dose (ED) of 6.2 mSv for the PET scans for each subject. From analysis of Step 2 and Step 3 
subjects, the recommended parameters for a Phase 2 study would be: approximately 185 MBq 
[18F]Flutemetamol, scanning start time approximately 90 minutes post injection, scan duration 
approximately 30 minutes, and data acquisition in 5 minute bins. 
 
Safety Results for the ALZ103 Study 
[18F]Flutemetamol was safe and well tolerated. No deaths, SAEs, or withdrawals due to AEs 
occurred during the study. There was no specific AE profile. Only 2 AEs (diarrhea and back pain) 
occurred during the study; both were mild in intensity, resolved during the study, and were deemed 
unrelated to [18F]Flutemetamol. Assessment of laboratory parameters (hematology, coagulation, 
serum biochemistry and urinalyses), vital signs and ECGs showed no clinically important trends or 
safety signals. One post-study SAE was reported after the study finished (a diagnosis of B-cell 
non-Hodgkin’s lymphoma in a HV 17 weeks after study completion). The relationship of 
[18F]Flutemetamol to this SAE was assessed as ‘not reasonable cause’. 
 
The results of ALZ103 have been published in two separate manuscripts. The first was the result of 
the Phase I study121 and the second was the radiation dosimetry.121 
 
5. TOXICITY and SAFETY OF FDG 
5. 1 Safety and Toxicity of FDG in Humans 
There are no known toxic effects of FDG. 
 

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6. Radiation Dosimetry of [18F]FLUTEMETAMOL and FDG PET/CT STUDIES 
6.1 Human Radiation Dosimetry for [18F]Flutemetamol 
The amount of injected [18F]Flutemetamol activity used in this protocol will be 185 MBq (5.0 
mCi). Higher administered doses have been used without safety or toxicity concerns. Please refer 
to the GE Healthcare IND # 101,866. The dosimetry for the compound was previously 
published.121 However, the dosimetry estimates for [18F]Flutemetamol have been revised in the 
recent FDA Product label and are used to estimate radiation dose and risks in this protocol. The 
greatest organ absorbed doses for a 185 MBq (5 mCi) injection of [18F]Flutemetamol are the 
gallbladder (53.1 mGy) and the bladder (26.83 mGy), while the effective dose is 5.92 mSv (Table 
3). 
 
6.2 Human Radiation Dosimetry for [18F]FDG 
The amount of injected [18F]FDG activity used in this protocol will be 370 MBq (10.0 mCi). This 
is the typical activity used for a clinical brain PET study and higher activities up to 740 MBq (20.0 
mCi) are used in whole-body oncology PET studies. The radiation dosimetry estimates for 
[18F]FDG are based on Publication 106 issued by The International Commission on Radiation 
Protection (ICRP).136 The greatest organ absorbed doses for a 370 MBq (10 mCi) injection of 
[18F]FDG are the bladder (48.1 mGy) and the heart (24.79 mGy), while the effective dose is 7.03 
mSv (Table 3). 
 
6.3 Human Radiation Dosimetry for CT-based Attenuation Correction for PET Imaging 
The study will be performed on the research GE Discovery 710 PET/CT scanner in the Molecular 
Imaging Suite at HCI.  Each PET imaging study will require CT imaging for attenuation 
correction.  Hence, there will be a total of 2 CT exams for each patient, one for the 
[18F]Flutemetamol-PET/CT study and another for the FDG-PET/CT.  After positioning the patient 
in the gantry of the PET/CT system, a topogram of the head will be obtained to confirm the correct 
positioning and identify the anatomic range for a single PET bed position covering the entire brain. 
A helical CT scan is then performed over the same anatomic range corresponding to the PET scan 
in order to perform for attenuation correction. The PET emission scan will commence immediately 
after the CT scan.  The CT acquisition parameters will be 120 kVp, 0.5s rotation speed, 50 mA 
tube current, 8 x 1.25 mm collimation, and a pitch of 1.35. This results in a CT Dose Index 
(CTDIvol) of 3.675 mGy based on a 16 cm phantom. A standard length of 1 PET bed position 
results in a Dose Length Product (DLP) of 61.92 mGy x cm. The estimated effective dose using 
the DLP scaling method is 0.13 mSv.137 In order to estimate the absorbed doses of individual 
organs and the resulting effective dose, the ImPACT Scan CT Patient Dosimetry Calculator 
(Version 1.0.4) was used with the specific acquisition parameters used in this protocol and the 
NRPB monte carlo dose data sets for the GE Lightspeed Ultra CT scanner produced in report 
SR250 dosimetry tables. Note that the topogram contributes a negligible radiation exposure to the 
helical CT exam. The greatest organ absorbed doses for a single head CT scan using the 

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Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
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aforementioned acquisition parameters are the eye lenses (3.5 mGy) and the brain (2.89 mGy), 
while the effective dose is 0.12 mSv (Table 3). 
6.4 Cumulative Radiation Dosimetry for [18F]Flutemetamol and [18F]FDG PET/CT Studies 
The cumulative radiation dose to a patient participating in this clinical trial has been compiled 
from the dosimetry estimates for [18F]Flutemetamol (Section 6.1), [18F]FDG (Section 6.2), and the 
2 head CT scans that will be performed as part of the PET/CT procedures. The greatest cumulative 
organ absorbed doses for the study are the bladder (74.9 mGy) and the gallbladder (57.9 mGy), 
while the effective dose is 13.2 mSv (Table 3).  
Table 3. Radiation Dosimetry for [18F]Flutemetamol and [18F]FDG PET/CT Studies 
 
 
 
7. RATIONALE, GOALS, AND HYPOTHESES 
7.1 Rationale and Goals of Study 
The primary goal of this study is to better understand the effects of chemotherapy on cognitive 
impairment in patients with breast cancer. Toward this end, we will be administering a variety of 
questionnaires and neuropsychological tests in addition to using two novel PET imaging agents 
([18F]Flutemetamol and FDG) and an anatomical MRI to assess the potential pathophysiology of 
CICI. 

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7.2 Significance  
The significance of this project is that we will investigate the possibility that amyloid plaque 
burden may have a major association to the cognitive dysfunction seen in some breast cancer 
patients with CICI. This study may help identify factors (such as, amyloid plaque burden), which 
may increase an individual’s risk of developing chemobrain. 
 
While one previous study has used FDG-PET and [15O]H2O-PET Imaging to assess cognitive 
function,7 to our knowledge there have been no studies that have used the combination of 
[18F]Flutemetamol, FDG, and MRI. Furthermore, we aim to investigate those individuals who are 
most likely to develop chemobrain and whether factors such as depression and anxiety, 
chemotherapy regimen, and coping mechanisms correlate with the development of CICI. 
 
7.3 Primary Endpoint 
Our primary hypothesis is that individuals with chemotherapy induced cognitive impairment will 
have a greater than expected amyloid plaque burden when compared to a control group of 
individuals who are not experiencing cognitive complaints. The chemotherapy may accelerate the 
process of amyloid plaque burden deposition and subsequent possible neuronal injury and loss in 
individuals who have undergone CICI. The primary endpoint will be amyloid plaque burden 
assessed by visual criteria as outlined in the recently approved Vizamyl (flutemetamol F 18 
injection) prescribing information.1 This will be a binary assessment of the images being positive 
or negative by visual criteria for abnormal [18F]Flutemetamol uptake. A secondary analysis of 
[18F]Flutemetamol binding will occur using a regional semi-quantitative technique as described by 
Vanderberghe et al.123 and Thufjell et al134. 
 
7.4 Exploratory Endpoints 
The following exploratory endpoints will be evaluated: 
Objective cognitive impairment correlated with subjective reports of cognitive impairment as 
measured by administered questionnaires. 
Amyloid plaque burden using regional semi-quantitative determinations is associated with greater 
objective cognitive impairment. 
Those individuals with the most profound cognitive impairment may have associated regional 
FDG metabolic changes consistent with neuronal loss or damage.  
 
8. STUDY DESIGN 
8.1 Overview of Study Design  
All enrolled subjects will complete three imaging sessions on separate days that consist of: 1) 
[18F]Flutemetamol-PET/CT, 2) FDG-PET/CT, and 3) MRI. The order of the performance of these 
studies will be based upon subject and radioisotope availability, but they will all be completed 

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Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
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within 2 months of each other. The total enrollment will be 12 evaluable patients (with all imaging 
sessions having been completed). 
 
8.2 Participant Eligibility 
Study participants: Female Adults (18 to 70 years of age) with previously diagnosed breast cancer 
Stage I through IIIC who have completed chemotherapy and who now report chemotherapy 
induced cognitive impairment. We expect that up to 15 total participants may be enrolled in this 
study. This will assure that 12 evaluable patients (patients who have complete imaging results and 
blood data available for data analysis. 
 
8.3 Inclusion Criteria  
• Female patients must be 18 years or older for inclusion in this research study. There is 
inadequate experience with the safety of [18F]Flutemetamol in children and therefore this 
radiopharmaceutical should not be used in patients under the age of 18. Individuals over 70 
years age will be excluded as the incidence of amyloid positivity increases significantly 
even with no cognitive problems and will not allow for testing of our primary hypothesis.  
• The patient must have a histologically proven diagnosis of Stage I through IIIC Breast 
Cancer. 
• The patient must have completed adjuvant chemotherapy more than 6 months ago, but no 
more than 36 months prior to initial study scan. 
• The patient must report persistent cognitive problems following the initiation of 
chemotherapy, defined as being one or more standard deviations above normative data on 
our two scales of subjective cognitive dysfunction.  This is defined as a total score of 45 or 
higher on the Cognitive Failure Questionnaire, and a T-score of 60 or higher on the Frontal 
System Behavioral Scale Questionnaire. 
• Patients must agree to have clinical and radiographic endpoints and the results of 
histopathologic tissue analysis and other laboratory information entered into a research 
database, as evidenced by signing the informed consent form. 
• All patients, or their legal guardians, must sign a written informed consent and HIPAA 
authorization in accordance with institutional guidelines. 
 
8.4 Exclusion Criteria 
• Patients with known allergic or hypersensitivity reactions to previously administered 
radiopharmaceuticals.  Patients with significant drug or other allergies or autoimmune 
diseases may be enrolled at the Investigator’s discretion. 
• Adult patients who require monitored anesthesia for PET scanning. 
• Patients who are too claustrophobic to undergo MRI or PET imaging. 

PI: Jeffrey Yap, PhD  
 
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Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
Version Date: 03/21/2024 
 
 
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• History of neurological disease known to affect cognition prior to initiating chemotherapy 
(e.g., stroke, head injury with loss of consciousness of >30 minutes, seizure disorder, 
demyelinating disorder, mental retardation, primary brain tumor, brain metastases, etc.) 
• Current or past major psychiatric illness (e.g., schizophrenia, bipolar affective disorder) 
• Evidence of stroke or mass lesion on CT or MRI scan 
• History of alcoholism or other substance abuse 
• Current use of cholinesterase inhibitors, other cognitive enhancers, antipsychotics, 
antidepressants, or anticonvulsant medications 
• Current use of gabapentin or venlafaxine for hot flashes 
• History of radiation therapy to the brain 
• Uncontrolled diabetes or blood glucose >175 mg/dl on the day of the FDG-PET scan 
• Currently pregnant 
• Color blindness (cannot complete D-KEFS Stroop test) 
• Moderate or Severe Depression as measured on the Beck Depression Inventory (BDI) –
Short Form. The cut-off score for the BDI will be 8/9. 
 
8.5 Participant Registration 
Participants must meet all of the eligibility requirements listed above and in Appendix A prior to 
registration.  
 
Study related screening procedures can only begin once the participant has signed a consent form. 
Participants must not begin protocol procedures prior to registration. 
 
To register eligible patients on study, a Clinical Trials Office Patient Registration Form will be 
completed and submitted to: CTORegistrations@hci.utah.edu. 
 
9 STUDY PROCEDURES, SCHEDULE of EVENTS, and TRACER ADMINISTRATION 
9.1 Initial Visits Prior to PET Imaging 
 
The patient will be screened using: Beck Depression Inventory Short Form to rule out Moderate to 
Severe Depression, and two subjective scales of cognitive functioning (Cognitive Failure 
Questionnaire and Frontal System Behavioral Scale). In addition, a review of the patient medical 
records will be conducted. The following patient data will be obtained: histological diagnosis 
(when available following surgery), age at radiological diagnosis, chemotherapy regime and date 
administered, current age and gender. 
 
9.2 Genetic Analysis 
We intend to investigate how genetics mediate measures of health-related quality of life and 
cognitive impairment in breast cancer patients. These factors are of interest because they may 

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Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
Version Date: 03/21/2024 
 
 
University of Utah IRB  
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contribute to chemotherapy-induced cognitive impairment. Prior to completing the first PET 
imaging scan, one tube of blood (5-7 ml) will be obtained for DNA analysis and APOe4 SNP 
genotyping. This will be labeled with patient study number.The DNA will be stored in the 
laboratory, and APOe4 genotyping will be done by ARUP. 
 
Genetic factors are of interest because it may be that chemotherapy merely accelerates age-related 
cognitive decline. According to this theory, those individuals who have a genetic predisposition 
toward the development of dementia or Alzheimer’s disease would be more likely to develop 
cognitive impairments associated with chemotherapy. One study has specifically linked the epsilon 
4 allele of APOE, a lipoprotein that has been studied for its role in Alzheimer’s disease, to 
significantly lower scores on tests of psychomotor functioning, visual memory and spatial ability 
in long-term breast cancer and lymphoma survivors.138 A blood draw for APOE assessment will be 
obtained prior to completion of the first PET imaging scan. No patient identifiers will be attached 
with the samples, and these results will not go into patient charts. Results will not be returned to 
participants. 
 
9.3 Neuropsychological Exams 
To assess memory, we will utilize the Hopkins Verbal Learning Test – Revised (HVLT-R) and the 
Brief Visuospatial Memory Test – Revised (BVMT-R). Processing speed will be tapped with Trail 
Making Test Part A (TMT-A) and the Coding and Symbol Search subtests of the Wechsler Adult 
Intelligence Scale – IV. Executive functioning will be measured with Trail Making Test Part B 
(TMT-B), Controlled Oral Word Association Test (COWAT), and Stroop Color Word Test 
(SCWT). Additionally, the Wide Range Achievement Test (WRAT4) will be used to assess 
premorbid intellect in all participants.  
 
9.4 Functional MRI Imaging 
Functional Magnetic Resonance Images (fMRI) will be obtained using a Siemens 3.0 Tesla whole-
body scanner equipped with a 32-channel multiband sed/receive head coil enabling rapid 
acquisition echo-planar imaging (EPI). Functional runs will consist of 405 frames per run 
[repetition time (TR) = 720 ms; echo time (TE) = 33.1 ms; flip angle = 52°, slice thickness = 2 
mm; FOV = 208 mm; matrix = 104x90; voxel size = 2.0 mm3] of 72 transverse slices per volume. 
The first three EPI volumes acquired during each functional run will be excluded from further 
analysis in order to allow for steady-state transverse relaxation. Coplanar high-resolution 
anatomical images will be acquired using a isotropic gradient echo (MPRAGE) sequence [TR = 
2.4s, TE = 2.14ms, TI = 1s, FA = 8, FOV = 224x224; vox size = 0.7 mm3] as well as an in-plane 
T2-weighted sequence [TR = 3.2 s; TE = 565 ms; FOV = 224x224 mm; slice thickness = 2 mm; 
matrix = 192 x 256] to allow precise localization of functional maps on brain anatomy. 
 
Stimuli will be recorded and presented using ePrime running on a laptop personal computer.  
Functional image volumes will be acquired according to a boxcar-type stimulus paradigm 

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Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
Version Date: 03/21/2024 
 
 
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consisting of alternating (A-B-A-B) stimulus-ON and stimulus-OFF conditions. Each functional 
run will consist of repeated cycles divided into two alternating stimulus-ON and stimulus-OFF 
epochs. During stimulus-ON epochs, stimuli will be presented, whereas no stimuli (silence) will be 
presented during stimulus-OFF epochs. In addition, each functional run will be preceded by a short 
period of silence during which three pre-experimental baseline EPI volumes will be acquired. 
While in the MR scanner, subjects will be instructed to attend to the stimulus being presented, and 
to perform the task according to functional protocols.   
 
Two functional runs will be collected according to the above protocol, using two independent task 
conditions designed to specifically probe higher cognitive functions implicated in chemobrain, 
namely working memory and relational processing. 
 
Working memory task: 
The category-specific representations are used to probe working memory during this task 
condition. Participants will be presented with blocks of trials that consist of pictures of places, 
tools, faces and body parts (non-mutilated parts of bodies with no “nudity”). Within each run, the 4 
different stimulus types will be presented in separate blocks. Within each run, 1⁄2 of the blocks use 
a 2-back working memory task and 1⁄2 use a 0-back working memory task (as a working memory 
load comparison). A 2.5 second cue indicates the task type (and target for 0-back) at the start of the 
block. Each of the two runs contains 8 task blocks (10 trials of 2.5 seconds each, for 25 seconds) 
and 4 fixation blocks (15 seconds). On each trial, the stimulus is presented for 2 seconds, followed 
by a 500 ms inter-task interval (ITI). Total scan time is 5:01. 
 
Relational Processing task: 
This task is adapted from Smith et al. 2007. Stimuli are 6 different shapes filled with 1 of 6 
different textures. In the relational processing condition, participants are presented with 2 pairs of 
objects, with one pair at the top of the screen and the other pair at the bottom of the screen. They 
are told that they should first decide what dimension differs across the top pair of objects (differed 
in shape or differed in texture) and then they should decide whether the bottom pair of objects also 
differ along that same dimension (e.g., if the top pair differs in shape, does the bottom pair also 
differ in shape). In the control matching condition, participants are shown two objects at the top of 
the screen and one object at the bottom of the screen, and a word in the middle of the screen (either 
“shape” or “texture”). They are told to decide whether the bottom object matches either of the top 
two objects on that dimension (e.g., if the word is “shape”, is the bottom object the same shape as 
either of the top two objects. For both conditions, the subject responds yes or no using response 
buttons. For the relational condition, the stimuli are presented for 3500 ms, with a 500 ms ITI, and 
there are four trials per block. In the matching condition, stimuli are presented for 2800 ms, with a 
400 ms ITI, and there are 5 trials per block. Each type of block (relational or matching) lasts a total 
of 18 seconds. There are 3 relational blocks, 3 matching blocks and 3 16-second fixation blocks. 
Total scan time is 2:56. 
 

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Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
Version Date: 03/21/2024 
 
 
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Local blood-oxygenation level-dependent (BOLD) image intensity signal changes will be analyzed 
to assess functional activation. SPM12 [Friston 1995] will be used for individual subject data 
analysis and visualization. Initially, a mean image from the central time-point of each functional 
run will be created for use in inter- and intra-scan head motion correction for each subject. The 
mean image will be used as the standard for re-registration of all 192 volumes.  All EPI images 
will then be smoothed with a Gaussian kernel of roughly 8 x 8 x 8 mm. Image intensities will be 
subsequently regressed to the mean in order to correct for signal drift associated with fluctuations 
of the B0 magnetic field. Noise outside the area of the brain will be excluded. EPI volumes will 
then be sorted into appropriate stimulus groups according to the experimental paradigm. To assess 
the extent of activation within the brain, a whole-brain analysis will be carried out using the full 
volume data set for both task conditions. Activation will be assessed by application of the General 
Linear Model as implemented in SPM12. The reference waveform will be composed of a boxcar 
waveform (essentially the stimulus paradigm) convolved with a Gaussian envelope of the same 
width. Correlation coefficient maps or statistical parametric maps of the t-statistic will be 
constructed and converted into Z-maps for subsequent cluster analysis. Clusters of activation will 
then be identified by considering both the extent and the magnitude of activation. Active voxel 
clusters will be subsequently thresholded at Family-Wise Error (FWE) corrected significance level 
of p < 0.05 (corresponding to Z-values >approximately 4.7) in order to statistically account for 
multiple comparisons. Finally, these clusters will be rendered onto the coplanar high-resolution 
MR images for precise anatomical localization. Significant clusters will be then used to compare 
activation across stimulus types and across subjects. 
 
Resting State fMRI (rsfMRI) 
Acquisition: 8 minutes of BOLD-EPI data will be collected with subjects lying in the scanner and 
instructed to simply 'lie still with your eyes open and think of nothing in particular'. We will 
concurrently monitor pulse oximetry and heart rate. These physiologic data serve two purposes: 
first, they serve as a ‘real-time’ proxy for assessment of subject discomfort and anxiety during the 
8 minute data collection run, as subjects will be instructed to try not to talk during the run (unless 
in distress). Second, these data provide covariates for motion-related assessment and correction at 
data analysis stages. Additional motion-related signal change will be assessed by averaging time 
courses for two ROIs in white matter, CSF, soft tissues of the head, face, and scalp, and corrected 
within SPM using these and six rigid-body motion correction parameters from the ‘Realign’ step, 
following previously published procedures in our lab (Anderson et al., 2011b). After motion 
correction, resulting frames will be inspected for significant motion using the “scrubbing” 
procedure reported by Power et al. (2012), and frames with temporal derivative of root-mean-
square variance over voxels (DVARS) or root-mean- square motion parameters >0.2 mm will be 
removed prior to analysis of connectivity results, with concatenation of remaining frames. 
 
Analysis: 8-minute BOLD EPI scans will be coregistered with high-resolution anatomical 
volumes, normalized, and bandpass-filtered between 0.01 and 0.1 Hz. Signal fluctuation within 4 
mm spherical seed regions of interest (ROI) representing major nodes within RSN hubs 
(representing sensorimotor, auditory, visual, speech, semantic, salience, executive function, and 

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Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
Version Date: 03/21/2024 
 
 
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Document Version:  010312 
default mode networks) will be cross-correlated with all other brain voxels. Correlation matrices 
will be constructed and significant pairwise correlation values will be represented in normalized 
brain space using subjects' anatomical MR image volumes. Groupwise network-level analyses will 
be carried out as above. 
 
9.5 PET Exams 
PET exams of [18F]Flutemetamol and [18F]FDG will be acquired in each participant. Two PET/CT 
scanning sessions will be required. This is due to fact that both [18F]Flutemetamol and FDG are 
labeled with F-18 that has a 110-minute half-life, which does not allow for same day imaging. The 
FDG and [18F]Flutemetamol study procedures will be obtained on separate days usually within 10-
14 days of each other. Typically these will be obtained over two separate days (consecutive if 
possible). However, this may not be possible due to scheduling issues, weekends, and other 
variables. The days of imaging will be scheduled according to scanner and cyclotron availability, 
and all days of imaging will be obtained within six weeks of each other. The exact order and 
timing of the two PET imaging sessions will vary according to logistics, scheduling, and tracer 
availability. Patients who are not postmenopausal for a minimum of one year or surgically sterile 
must have a serum pregnancy test performed within 48 hours prior to each research PET imaging. 
The procedures for each PET scan are similar as described below. 
 
9.5.1 Day of Research PET Scan(s) 
The patient will have the appropriate IV access placed for radiotracer administration. Access for 
temporal blood sampling, necessary for obtaining the input function for PET kinetic modeling, will 
be obtained using the heated-hand methodology for obtaining arterialized venous blood (FDG). 
The patient will be positioned comfortably on the PET imaging table. After positioning the patient 
in the gantry of the GE Discovery 710 PET/CT system, a topogram of the head will be obtained to 
confirm the correct positioning and identify the anatomic range for a single PET bed position 
covering the entire brain. A helical CT scan is then performed over the same anatomic range 
corresponding to the PET scan in order to perform attenuation correction. Thereafter the PET scans 
will then be acquired for either the dynamic FDG PET study or the static [18F]Flutemetamol PET 
study. 
 
9.5.2 PET Tracer Administration Overview 
 
Table 4.  PET Tracer Administration:  Route, Dosing, and Blood Sampling 
Tracer 
Route 
Manner 
Injected 
Dose 
Scan Mode 
Blood 
Sampling 
18F-FDG 
IV 
~60s push 
~10.0 mCi  
Dynamic 
Heated-hand 
[18F]Flutemetamol 
IV 
~30s push 
~5.0 mCi  
Static 
N/A 
 

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Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
Version Date: 03/21/2024 
 
 
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Each radiopharmaceutical will be prepared by the investigational drug radiochemists in the PET 
cyclotron facility at HCI on the day of the scanning session. It will be administered to the patient 
by a physician, nuclear medicine technologist, or trained nurse in the research PET imaging suite.  
The dynamic imaging procedure will take 70 minutes to complete for FDG.  
 
No adverse events have ever been reported with the use or administration of FDG so reporting is 
not required.   
 
9.6 Tissue Collection and Analysis 
All patients enrolled on this study may have recent surgical pathology or biopsy information 
available and tissue specimen reports and assessments will be analyzed by the study PI and co-
investigators.  
 
10. METHODS FOR EVALUATION OF IMAGING STUDIES/ DATA ANALYSIS AND 
STATISTICS 
Each PET imaging study will be evaluated using qualitative, semi-quantitative, and fully-
quantitative analysis techniques that have previously been evaluated by us and other 
groups116,139,140 and represent the standard and accepted means of evaluating static- and dynamic-
PET images for these tracers.  These assessments are described below for each tracer. 
 
10.1 18F-FDG-PET Imaging  
10.1.1 FDG Semi-Quantitative Assessment 
FDG-PET data will be analyzed using CortexID Suite, a software application provided by GE 
Healthcare. The software has a large group of normal healthy controls of varying ages included as 
the normal database so the provided Z scores are in comparison to age and sex matched controls. 
Cortex ID Suite is an FDA approved brain image analysis software designed to quantify FDG 
uptake measured with PET and PET-CT brain scans. The software aids clinicians in the assessment 
of FDG-PET scans by providing automated analysis through quantification of the comparison of 
local peak FDG uptake activity values, at standardized bilateral anatomical locations, compared 
with the corresponding reference normal peak activity in age- stratified normal control subjects. 
The resulting quantification is presented through 3D Stereotactic Surface Projection (SSP) maps of 
the brain as initially described by Minoshima et al.141 CortexID allows for user generated 
information on the relative changes in metabolic activity normalized to the pons presented as 
regional and global Z-scores between a subject's images and age-stratified controls. The regions of 
interest that will be assessed include: parietal association, temporal association, frontal association, 
occipital association, posterior cingulate, anterior cingulate, medial frontal, medial parietal, visual, 
cerebellum, pons, average association, averaged cerebral, global average. 
 

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Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
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10.1.2 FDG Fully-Quantitative Assessment 
Compartment modeling techniques will be applied to the dynamic PET data to obtain estimates of 
kinetic rate parameters (K1, k2-k4) and FDG net uptake (Knet). Individual rate parameters will be 
computed using full compartment-modeling techniques according to the two-tissue compartment 
model shown below. The commercially available PET analysis software (e.g. PMOD Technologies 
LTD., Zurich, Switzerland) will be used. The net uptake parameter will be computed from both 
full compartment modeling and Patlak graphical analysis139,140 both of which are standard and 
accepted methods. 
 
 
 
A region-of-interest (ROI) will be drawn over the defined cortical brain region on the summed 
static FDG PET image. The summed image will be co-registered and fused to the patient’s MRI. 
This will allow for regional determination of brain glucose metabolic rates. For each ROI the 
metabolic rate obtained can then be correlated with available clinical data, neuropsychological 
data, and the regional amyloid plaque burden SUV. 
 
10.2 [18F]Flutemetamol-PET Imaging 
The primary assessment of amyloid plaque burden will be with visual assessment of abnormal 
cortical flutemetamol uptake as outlined in the recently approved Vizamyl (flutemetamol F 18 
injection) prescribing information (section 2.5).1 This will be a binary assessment of the images 
being positive or negative for increased and abnormal flutemetamol uptake and thus increased 
amyloid plaque burden. A secondary analysis of flutemetamol binding will occur using a regional 
semi-quantitative technique as described by Vanderberghe et al.123 In this technique, a semi-
quantitative global composite of standardized uptake value ratios (SUVRs) in the cerebral cortex 
which is obtained and normalized to the cerebellum or pons. The following regions are averaged to 
yield the global composite: lateral frontal, lateral temporal, lateral parietal, anterior cingulate, and 
posterior cingulate. This will yield a global composite for [18F]Flutemetamol-PET data.  GE 
proprietary software (CortexID Suite) is available in our laboratory and will be used to determine 
both regional SUV values and a composite SUVR for [18F]lutemetamol uptake. This database also 
contains [18F]Flutemetamol scan data from 105 healthy volunteers and has been validated to be 
over 99% concordant with visual reads using 172 scans from AD, MCI, and healthy controls using 
a threshold Z score of 2 (which corresponds to a composite SUVR of 0.59). This software will 
provide the control population to which we will compare our symptomatic CICI patients. Z scores 
obtained for the study patients using this software will then be correlated with available clinical 
data, neuropsychological data, and the regional FDG Z scores or metabolic rates.    
 
Plasma
FDG
Cellular
FDG
K1
FDG
k2
FDG
Cellular
FDG-6-PO4
k3
FDG
k4
FDG

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Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
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10.3 Magnetic Resonance Imaging 
Participants will be imaged using a Siemens Trio 3T MRI scanner with 32 channel head coil using 
a magnetization prepared rapid gradient echo (MPRAGE) acquisition with isotropic image 
resolution of 1.0 mm and full head field of view. Imaging will be performed in the sagittal plane 
with repetition of sequences deemed at the time of acquisition to exhibit patient head motion or 
other artifacts. Images will be analyzed using SPM12 toolbox for MATLAB, with linear 
normalization to Montreal Neurological Institute (MNI) template brain space, segmentation of 
gray matter, white matter, CSF, and volumetric quantitation of gray matter voxels and gray matter 
density compared to previously acquired control cohorts using the same sequence, with age-
matched normative database. Regions of abnormal volume and density will be identified in 116 
regions of the automated anatomical labeling (AAL) brain atlas. 
 
10.4 Data Analysis 
The primary hypothesis is that individuals with chemotherapy induced cognitive impairment 
(CICI) will have a greater than expected amyloid plaque burden when compared to a control group 
of individuals who are not experiencing cognitive complaints. It is hypothesized that increased and 
abnormal [18F]Flutemetamol uptake will be present in individuals with CICI. The primary analysis 
will be an exact one sample binomial test based on a composite SUVR of 0.59 (Z-score =2) 
provided by the CortexID software from GE Healthcare. A Z-score greater than or equal to 2.0 
(composite SUVR greater than or equal to 0.59) will be coded as a positive amyloid scan and a Z 
score less than 2.0 (composite SUVR less than 0.59)134 will be coded as negative. In clinical 
practice visual analysis is the standard approach for assessing amyloid positivity. This provides a 
simple binary positive or negative visual assessment of flutemetamol uptake. Since the visual 
approach is the standard used in clinical interpretation (Vizamyl prescribing information - section 
2.5)1  we will also perform a secondary visual analysis to compare with the more quantitative 
SUVR approach to assess for correlation between the composite SUVR and visual binary analysis 
methods. This is an exploratory analysis independent from the primary binary determination of 
amyloid positivity based on the composite SUVR. The prevalence of amyloid plaque burden in 
cognitively normal elderly individuals is up to 33% depending on the amyloid imaging agent used, 
patient age, and criteria used for evaluation.1,142-145 However, using [18F]Flutemetamol in a slightly 
younger population, Vandenberghe al. found that in a group of fifteen cognitively intact healthy 
volunteers over 55 (mean age 68.7) only one healthy volunteer had a positive amyloid scan.123 
 
The following exploratory endpoints will also be also evaluated: 
I. 
Objective cognitive impairment correlated with subjective reports of cognitive impairment 
as measured by administered questionnaires. 
II. 
Amyloid plaque burden using regional semi-quantitative determinations is associated with 
greater objective cognitive impairment. 
III. 
Those individuals with the most profound cognitive impairment may have associated 
regional FDG metabolic changes consistent with neuronal loss or damage.  
 

PI: Jeffrey Yap, PhD  
 
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Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
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Previous Version Date: 01/11/2021 
Version Date: 03/21/2024 
 
 
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The imaging parameters will include the Z score values from Cortex ID for FDG and Z scores, 
regional SUV values and the composite SUVR for [18F]lutemetamol from CortexID.146 For FDG 
these particular values are in comparison to an age-matched cohort so by definition they define a 
degree of FDG uptake reduction from normal. For [18F]Flutemetamol there is no specific age-
related deposition in the database to assess age-matched normality so the study images will be 
compared the database control group as a whole to determine the Z scores compared to clinically 
negative amyloid scans. Z score values both regional and global for FDG and composite 
([18F]Flutemetamol) can then be correlated with the various neuropsychological variables and 
clinical variables obtained to assess for differences and trends. The data will be analyzed 
descriptively using summary statistics and paired t-tests.  Means, standard deviations and 
confidence intervals will also be reported. Scatterplots and bivariate summaries such as Pearson 
correlation coefficient and scatterplots will be used to characterize pairs of imaging parameters. 
 
10.5 Justification of Sample Size 
Twelve evaluable patients (defined as having complete imaging and blood data available) will be 
enrolled in this study. By definition, 100% of evaluable patients enrolled will receive the complete 
set of PET studies [18F]Flutemetamol, FDG, and MRI. Due to blood drawing issues the total 
enrollment will need to be approximately 15 subjects to assure that complete blood and imaging 
data sets in 12 participants will be available for analysis. The data from Vandenberghe al. found 
that in a group of fifteen cognitively intact healthy volunteers over 55 (mean age 68.7) only one 
healthy volunteer had a positive amyloid scan.123 Based on this data using a population similar in 
age to the expected experimental cohort, our null hypothesis (H0) is that 12% of study participants 
will have amyloid positivity. With 12 patients we will have 80% power to reject H0 at the nominal 
0.05 one-sided significance level provided the true proportion of subjects with amyloid positivity 
is 42%. The null hypothesis will be rejected if 4 or more out of 12 patients show amyloid 
positivity. We will not image a separate control population in this study. The CortexID software 
contains a database of [18F]Flutemetamol scan data from 105 healthy volunteers134 and will serve 
the function of a control group for the purposes of this exploratory study. The CortexID database 
has been validated in a subsequent study using [18F]Flutemetamol scans from 345 AD, MCI, or 
cognitively normal individuals.134  
 
11. REGULATORY AND REPORTING REQUIREMENTS 
This study involves exposure to radiation and is appropriate for Human Use Subcommittee 
Review. FDG-PET is a clinically approved procedure for patients with cancer. However, for this 
research study, FDG is being performed under IND# 113,858 and [18F]Flutemetamol is being 
performed under IND#109,760 (Yap is IND holder for both INDs), as such the following FDA 
reporting of unexpected fatal or life threatening events, serious adverse events, and serious and 
unexpected adverse events will occur: (1) reporting any unexpected fatal or life threatening 
adverse experience associated with the use of [18F]Flutemetamol by telephone or fax no later than 
7 calendar days after initial receipt of the information. (2) Reporting any adverse experience 
associated with the use of [18F]Flutemetamol, that is both serious (SAE) and unexpected in writing 

PI: Jeffrey Yap, PhD  
 
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Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
Version Date: 03/21/2024 
 
 
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no later than 15 calendar days after initial receipt of the information. (3) Submitting annual reports. 
The reportable events will also be submitted to the IRB using the University of Utah ERICA 
online system:  
https://erica.research.utah.edu/erica/Rooms/DisplayPages/LayoutInitial?Container=com.webridge.
entity.Entity%5BOID%5B5FD2DA60262617429607E459C0E09D92%5D%5D 
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03 will be utilized for adverse event reporting 
(http://ctep.cancer.gov/reporting/index.html). 
 
All appropriate research areas will have access to a copy of the CTCAE version 4.03 with 
modifications. A list of adverse events that have occurred or might occur (Reported Adverse 
Events and Potential Risks) can be found in Section 6 (Imaging Studies Information). 
 
The reportable events will also be submitted to the IRB using the University of Utah ERICA 
online system:  
https://erica.research.utah.edu/erica/Rooms/DisplayPages/LayoutInitial?Container=com.webridge.
entity.Entity%5BOID%5B5FD2DA60262617429607E459C0E09D92%5D%5D 
 
Adverse events will be assessed for [18F]Flutemetamol immediately following the imaging scan. 
Additionally, a follow-up telephone call will be made to each participant within 1 day following 
their imaging scan. If the participant cannot be contacted at 1 day post-scanning, then we will 
continue trying to contact them for up to 7 days post-scanning.  
 
11.1 Expedited Adverse Event Reporting 
Those adverse events which are not associated with [18F]Flutemetamol do not require expedited 
reporting and will be reported in the routine manner to the IRB. Adverse event reporting is only 
required for events within 24 hours from the time of the injection of the experimental imaging 
agents [18F]Flutemetamol.  
 
11.2 Expedited Reporting Guidelines – Phase 1/2 studies with Investigational Agents 
The guidelines given in Table 5 below will be followed. Any unexpected fatal or life threatening 
adverse experience associated with the use of  [18F]Flutemetamol will be reported to the FDA by 
telephone or fax no later than 7 calendar days after initial receipt of the information. All reportable 
adverse events will be submitted to the FDA & IRB within the required timeframe by as mandated 
by the FDA and IRB. Hospitalization will be defined as any medical event equivalent to CTCAE 
grade 3, 4, or 5 that precipitated hospitalization (or prolongation of existing hospitalization). 
Adverse event reporting is only required for events within 24 hours from the time of the injection 
of the experimental imaging agent [18F]Flutemetamol.  
 

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IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
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Table 5. 
 
UNEXPECTED EVENT 
EXPECTED EVENT 
 
GRADES 3 
Attribution of 
Possible, Probable or 
Definite 
 
GRADES 4 and 5 
Regardless of 
Attribution 
 
GRADES 1 - 3 
 
GRADES 4 and 5 
Regardless of 
Attribution 
 
Expedited report 
within 10 working 
days. 
 
(Grade 1or 2 Adverse 
Event Expedited 
Reporting NOT 
required.) 
 
Report to FDA 
 
Report to HCI DSMC 
 
Expedited report to 
follow within 7 
working days. 
 
Any late death 
attributed to the agent 
(possible, probable, or 
definite) should be 
reported within 7 
working days. 
 
Report to FDA 
 
Report to HCI DSMC 
 
 
Adverse Event 
Expedited 
Reporting NOT 
required. 
 
Expedited report within 7 
working days. 
 
Any late death attributed 
to the agent (possible, 
probable, or definite) 
should be reported within 
7 working days. 
 
Report to FDA 
 
Report to HCI DSMC  
 
For Hospitalization only – Any medical event equivalent to CTCAE grade 3, 4, or 5 that 
precipitated hospitalization (or prolongation of existing hospitalization) must be reported 
regardless of designation as expected or unexpected and attribution. 
 
11.3 Expedited Expected Adverse Event Reporting Exclusions 
For this protocol, the following adverse events are specifically excluded from expedited AE 
reporting:  None 
 
Note: All deaths on study will be reported using expedited reporting regardless of causality.  
Attribution to treatment or other cause will be provided. 
Fatal and life-threatening events will be reported to the IRB within 24 hours of notification of the 
event, indicating that a full report will follow. Any unexpected fatal or life threatening adverse 
experience associated with the use of  [18F]Flutemetamol will be reported to the FDA by telephone 
or fax no later than 7 calendar days after initial receipt of the information. All reportable adverse 

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events will be submitted to the FDA & IRB within the required timeframe by as mandated by the 
FDA and IRB.  
11.4 Data Reporting 
A Data and Safety Monitoring (DSMC) is established at Huntsman Cancer Institute (HCI) and 
approved by the NCI to assure the wellbeing of patients enrolled on Investigator Initiated Trials 
that do not have an outside monitoring review. Roles and responsibilities of the DSMC are set 
forth in the NCI approved plan. The activities of this committee include a quarterly review of 
adverse events including SAEs, important medical events, significant revisions or amendments to 
the protocol, and approval of cohort/dose escalations. If the DSMC and/or the PI have concerns 
about unexpected safety issues, the study will be stopped and will not be resumed until the issues 
are resolved. The DSMC also reviews and approves audit reports generated by the Research 
Compliance Office.  
 
This study is considered a low risk trial per the DSMC plan.  All low risk studies are audited no 
less than annually by the Research Compliance Office and audit reports will be reviewed and 
approved by the full DSMC.  The DSMC will also review all Serious Adverse Events for patients 
on this study.  
11.5 Reporting Protocol Violations/Deviations 
A protocol deviation (or violation) is any departure from the defined procedures and treatment 
plans as outlined in the protocol version submitted and previously approved by the IRB.  Protocol 
deviations have the potential to place participants at risk and can also undermine the scientific 
integrity of the study thus jeopardizing the justification for the research. Protocol deviations are 
unplanned and unintentional events.   
 
Because some protocol deviations pose no conceivable threat to participant safety or scientific 
integrity, reporting is left to the discretion of the PI within the context of the guidelines below.  
The IRB requires the prompt reporting of the following protocol deviations: 
• Exceptions to eligibility criteria 
• Intended to eliminate apparent immediate hazard to a research participant or 
• Harmful (caused harm to participants or others, or place them at increased risk of harm - 
including physical, psychological, economic, or social harm) or 
• Possible serious or continued noncompliance  
Annual progress reports will be submitted to the FDA within 60 days of the date that the IND was 
effective/or approved. 
 
12. ETHICAL AND REGULATORY REQUIREMENTS 
12.1 Informed consent 
Informed consent will be obtained from all research participants prior to performing any study 
procedures using the most recent IRB approved version.  

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12.2 Institutional Review 
This study will be reviewed and approved by the Institutional Review Board of University of Utah 
prior to any participants being enrolled on the study. 
 
12.3 Reported Adverse Events and Potential Risks 
Blood sampling entails the risks of minor discomfort, infection, bruising and bleeding.  Radiation 
risk accompanies the use of radioisotopes in PET imaging. FDG-PET imaging is considered to be 
generally safe and effective. It has been approved by the Centers for Medicare and Medicaid for 
several clinical indications, using procedures identical to those used in this study. FDG is 
administered in trace doses and adverse effects have not been reported during it’s more than 20 
years of use. Nevertheless the possibility exists for a rare allergic reaction.   
 
The current use of [18F]Flutemetamol is investigational although it did receive FDA approval in 
October 2013. To date, it has been given to numerous individuals world-wide at the doses 
proposed here without significant adverse effect.122 Subjects scanned with PET are exposed to 
radiation. The amount of radiation exposure will be well within limits permitted to radiation 
workers by federal regulations. There is no known minimum level of radiation exposure that is 
recognized as being totally free of the risk of causing genetic defects (cellular abnormalities) or 
cancer.  However the risk associated with the amount of radiation exposure that the subject will 
receive from this study is considered to be low.   
 
Radioisotope injection requires the use of an intravenous catheter. There is a minimal risk of 
infection and bruising associated with the venipuncture required for the indwelling catheter. There 
can be discomfort from the requirement from lying quietly during imaging. Research data includes 
personal health information that can be inadvertently revealed to others. All of these risks are 
similar to those encountered during usual clinical care. 
For the MRI, the risks are expected to be minimal. There is a protocol to follow prior to imaging, 
which includes a rigorous screening by specially trained MR personnel to avoid the risks listed 
below. All MR imaging will occur in the Imaging and Neurosciences Center at the University of 
Utah under the supervision of a Neuroradiologist. If individuals have any MRI incompatible metal 
pieces in their body, these metal pieces could potentially move during the scan and damage nearby 
tissues or organs. Transdermal patches also may contain metal and may cause burns if they are not 
removed from the skin before the scan. There can be a feeling of claustrophobia associated with 
the procedure; if participants experience anxiety from a feeling of claustrophobia, they can tell the 
researcher. Individuals can be removed from the scanner and given the option to terminate the 
study, if they become uncomfortable for any reason. 
We will strive to maintain confidentiality of all participants enrolled in the study. All paper 
research data will be stored in a locked file cabinet. All electronic data will be stored on password-
protected computers. All research data will be de-identified. Finally, all participants will be 
assigned a unique identification number to use in place of their name on all study data. 
 

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12.4 Agent Accountability 
Each radiosynthesis is done by University of Utah cyclotron and radiochemistry staff and the 
product [18F]Flutemetamol in a dose calibrated syringe will be released after passing all required 
quality control assays to the physician who will be responsible for administering the appropriate 
amount (John M. Hoffman, MD or his designee). The quality control tests that must be passed 
prior to release of the product [18F]Flutemetamol for injection include the radioactive purity, the 
radiochemical purity, sterilizing filter integrity, pyrogens, and particulates. The [18F]Flutemetamol 
dose is drawn up into a syringe, assayed for mCi at the time of injection, and administered to the 
research subject. Any remaining compound from the synthesis will be allowed to decay and 
destroyed per our facilities standard operating procedures.  
 
12.4.1 [18F]Flutemetamol 
Flutemetamol is a radiopharmaceutical that is produced in the cyclotron facility at the Huntsman 
Cancer Institute. The agent is investigational and approved by the FDA under IND #109,760.  
 
12.4.2 [18F]FDG 
FDG is a radiopharmaceutical that is produced in the cyclotron facility at the Huntsman Cancer 
Institute. The agent is investigational and approved by the FDA under IND # 113,858.  

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13. REFERENCES 
 
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14.    APPENDICES 
 
 
APPENDIX A 
 
Eligibility Check List and Current Drug Use and Potential Toxicities 
 
APPENDIX B 
Current Drug Use and Potential Toxicities 
 
APPENDIX C  
MRI Patient History and Safety Screening 
 
 
 
 
APPENDIX D 
Schedule of Events 
 
             
 
APPENDIX E 
[18F] Flutemetamol Patient Adverse Event Questionnaire 
 
GE Healthcare Pregnancy Reporting Form 
 
 
APPENDIX F 
 
NCI Common Toxicity Criteria 
 
APPENDIX G 
 
GE Healthcare Pregnancy Reporting Form 
 
 
APPENDIX H 
 
GE Healthcare SAE Reporting Form 
 
 
APPENDIX I 
 
GE Healthcare Supplemental Safety Reporting Form 
 

PI: Jeffrey Yap, PhD  
 
     Page 57 of 73 
Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
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APPENDIX A:  Eligibility Check List and Current Drug Use and Potential Toxicities 
 
Patient Name: 
___________________________________      Date: _________________
 
 
 
MRN: __________________ Person Confirming Eligibility _____________________________ 
 
_____ (Yes/No)   Patient is female. 
 
_____ (Yes/No)   Patient is ≥ 18 years old. 
 
_____ (Yes/No)   Patient is < 70 years old. 
 
_____ (Yes/No)   Patient has a histologically proven diagnosis of Stage I through III C breast 
cancer  
 
_____ (Yes/No)   Patient has been previously treated with chemotherapy at least 6 months prior, 
but no more than 36 months prior to initial study scan. 
 
                             Dates: _______________________________________ 
                              
                             Type of Chemotherapy:_____________________________________________ 
_____ (Yes/No)   Patient must be postmenopausal for a minimum of one year, surgically sterile, or 
has been confirmed not to be pregnant by serum pregnancy test performed within 48 hours prior to 
research PET imaging. 
 
 
            If patient is postmenopausal, how far out are they from menopause: ___________ 
 
 
 
If patient is of childbearing potential, date of negative pregnancy test:  __________ 
_____ (Yes/No)   Patient is not lactating. 
 
_____ (Yes/No)   Patient has no history of previous stroke, seizures, or other neurological 
disorders. 
 
_____ (Yes/No)   Patient agrees to have clinical and radiographic endpoints and results of 
histopathologic tissue analysis and other laboratory information entered into a research database, 
as evidenced by signing the informed consent form.  
 
_____ (Yes/No)   Patient does not have allergic or hypersensitivity reactions to previously 
administered radiopharmaceuticals. 
 
_____ (Yes/No)   Patient does not require monitored anesthesia for PET scanning or MRI imaging. 

PI: Jeffrey Yap, PhD  
 
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Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
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_____ (Yes/No)   Patient is not too claustrophobic to undergo MRI or PET imaging. 
 
_____ (Yes/No)   Patients is able to lie still for 60 minutes. 
 
 _____ (Yes/No)   Patient does not have any MRI incompatible metal implants or clips. 
 
_____ (Yes/No)   Patient has not been diagnosed with dementia or any other cognitive 
deteriorating conditions. 
 
_____ (Yes/No)   Does patient have a family history of dementia? (Does not preclude participation 
in study) 
 
_____ (Yes/No)   Is the patient right handed? (Informational for set up of fMRI study) 
 
_____ (Yes/No)   Patient is not moderately or severely depressed as measured on the Beck 
Depression Inventory (BDI) –Short Form. 
 
_____ (Yes/No)   Patient must report persistent cognitive problems following the initiation of 
chemotherapy, defined as being one or more standard deviations above normative data on our two 
scales of subjective cognitive dysfunction 
 
• Cognitive Failure Questionnaire Score:  ____________   (Total score 45 or higher)___ 
 
• Frontal System Behavioral Scale Score:  ____________  (T-score of 60 or higher) 
 
_____ (Yes/No)   Patient is not currently using gabapentin or venlafaxine for hot flashes. 
 
_____ (Yes/No)   Patient is not currently using cholinesterase inhibitors, other cognitive enhancers, 
antipsychotics, antidepressants or anticonvulsant medications. 
 
_____ (Yes/No)   Patient is not color blind. 
 
_____ (Yes/No)   Patient has no history of radiation therapy to the brain, any current or past major 
psychiatric illness, or a history of alcoholism or other substance abuse. 
 
_____ (Yes/No)   Patient does not have a current or past major psychiatric illness such as 
schizophrenia or bipolar affective disorder. 
 
 
 
 
 

PI: Jeffrey Yap, PhD  
 
     Page 59 of 73 
Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
Version Date: 03/21/2024 
 
 
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Comments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I certify that this patient meets all inclusion and exclusion criteria for enrollment onto this study. 
 
 
________________________________________ 
 
_________ 
        _______ 
Investigator Signature  
 
 
 
 
Date 
 
        Time 
 
 
 

PI: Jeffrey Yap, PhD  
 
     Page 60 of 73 
Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
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Appendix B: Current Drug Use and Potential Toxicities 
 
Current Drug Use and Potential Toxicities 
Drug 
 
Neuropathy 
Hematologic 
Hepatic  
Other prominent 
toxicity (note it) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Completed by ___________________________     Date: _______________ 
 
 

PI: Jeffrey Yap, PhD  
 
     Page 61 of 73 
Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
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APPENDIX C: MRI Patient History and Safety Screening 
 
MRI PATIENT HISTORY & SAFETY SCREENING 
Please print 
Date  _________________________ 
                Patient MRN_________________________ 
 
Name  _______________________ _________________________   
 
 
Patient Height_________Weight_________ 
Date of Birth  _____________________  Age  _________   ReferringPhysician_________________________ 
DO YOU HAVE AN APPOINTMENT WITH YOUR DOCTOR TODAY?  _______If yes, at what time?__________ 
IMPORTANT INSTRUCTIONS: You may be asked to change into hospital clothing for purposes of MRI safety.  A 
locker will be provided.  Please remove ALL metallic objects such as hearing aids, dentures, partial plates, keys, cell 
phone, eyeglasses, hair pins/clips , jewelry, body piercing jewelry, watch, safety pins, magnetic strip cards and 
clothing with metallic fasteners, threads or fibers including some sportswear tech fabrics.  If you have any 
questions, please ask a technologist BEFORE entering the MRI scan room. 
□ Yes  □ No 
 Cardiac Pacemaker (If yes, Stop and inquire with MRI personnel) 
□ Yes  □ No   Implanted Cardiac Defibrillator (ICD) (If yes, Stop and inquire with MRI personnel) 
□ Yes  □ No 
 Breast Tissue Expanders (If yes, Stop and inquire with MRI personnel) 
□ Yes  □ No 
Spinal cord stimulator (If yes, Stop and inquire with MRI personnel) 
□ Yes  □ No 
Swan-Ganz Thermo Dilution catheter (If yes, Stop and inquire with MRI personnel) 
□ Yes  □ No 
Acticoat Silver Wound Dressing (If yes, Stop and inquire with MRI personnel) 
□ Yes  □ No 
Cochlear Inner Ear Implant (If yes, Stop and inquire with MRI personnel) 
□ Yes  □ No 
Stapes Inner Ear Implant 
□ Yes  □ No 
Brain Aneurysm Stents, Clips or Coils Type ___________________ 
□ Yes  □ No 
 Electronic or Magnetic Implant, Neurostimulator (tens unit, bone growth, etc.)  
□ Yes  □ No 
Internal electrodes or wires 
□ Yes  □ No 
Aortic or Carotid Artery Clips 
□ Yes  □ No 
Hearing Aid (Remove before entering MRI scan room) 
□ Yes  □ No 
Insulin pump or Implanted Infusion device Type ____________ 
□ Yes  □ No 
Heart Valve or Cardiac Stent 
□ Yes  □ No 
Shunt, intraventricular or spinal 
□ Yes  □ No 
Vascular Coil, Umbrella Filter, or other Stent 
□ Yes  □ No 
Vascular Access Port or I.V. Catheter 
□ Yes  □ No 
Prosthetic device (Limb, Joint, Eye, etc.) Type ________________ 
□ Yes  □ No 
Joint replacements (Hip, Knee, etc.) Location ________________ 
□ Yes  □ No 
Metal (circle)   Rods,   Plates,   Screws,   Nails,   Pins,   Clips,   Other Location______________ 
□ Yes  □ No 
Shrapnel (Metal Fragments) or Gunshot Injury Location ________________ 
□ Yes  □ No 
Metal Fragments in eye past or present (History as Grinder, Welder, Machinist, etc.) 
□ Yes  □ No 
IUD, Diaphragm, Penile Implant 
□ Yes  □ No 
Eyelid Spring, Wire, Gold Weight 
□ Yes  □ No 
Medication Patch (Remove before entering MRI scan room) 
□ Yes  □ No 
Wire Mesh Implant 
□ Yes  □ No 
Removable Denture or Retainer 
□ Yes  □ No 
Tattoos (Cosmetic, Body) 
□ Yes  □ No 
Body Piercings Location ___________________________ 

PI: Jeffrey Yap, PhD  
 
     Page 62 of 73 
Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
Version Date: 03/21/2024 
 
 
University of Utah IRB  
Document Version:  010312 
□ Yes  □ No 
Biopsy Markers or Breast Implants: Type____________________  
□ Yes  □ No 
Hair Pins or Hair Piece / Wig (Will need to be removed before entering MRI scan room) 
□ Yes  □ No 
Bronzing / Tanning Lotions 
□ Yes  □ No 
Other Implants (Pill Camera, Tooth, etc.) Type ______________________ 
 
I attest that the above information is correct to the best of my knowledge. I read and understand the contents of this 
form and had the opportunity to ask questions regarding the information on this form and regarding the MR procedure 
that I am about to undergo. 
 
Signature of Person Completing Form:_________________ 
________________________________ 
 
 
Print Name:____________________                                                                         Date:____/_____/______ 
 
Form Completed By:  Patient  Guardian  Relative  Nurse/Physician 
 
 
 

PI: Jeffrey Yap, PhD  
 
     Page 63 of 73 
Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
Version Date: 03/21/2024 
 
 
University of Utah IRB  
Document Version:  010312 
APPENDIX D:  Schedule of Events 
 
Test / Procedure 
Screen 
Research 
MRI study 
and Neuro-
psychological 
Testing 
PET Imaging Visit 1 
First PET Exam 
Will depend on 
whether [18F]-
Flutemetamol or FDG 
study is performed 
PET Imaging Visit 2 
Second PET Exam 
Will depend on 
whether [18F]-
Flutemetamol or 
FDG study is 
performed 
Inclusion / 
Exclusion Criteria 
X 
 
 
 
Informed Consent 
X 
 
 
 
Research MRI 
study 
 
 
X 
 
 
Infusion of 
[18F]Flutemetamol 
 
 
X 
X 
[18F]Flutemetamol  
PET Imaging 
 
 
X 
X 
Adverse Event 
Questionnaire 
After 
[18F]Flutemetamol 
study 
 
 
X (3)* 
X (3)* 
18F-FDG PET 
Imaging 
 
 
X 
X 
Neuropsychological 
Testing 
 
X 
 
 
Pregnancy Test (1) 
 
 
X (2) 
X (2) 
* 
1 
 
 
2 
 
 
 
3 
Performed immediately after 1[18F]Flutemetamol study 
Patient must be postmenopausal for a minimum of one year, surgically sterile, or has 
been confirmed not to be pregnant by serum pregnancy test performed within 48 hours 
prior to research PET imaging. 
GE requires all pregnancies that occur within 30 days of exposure to the 
investigational product be submitted to their institution.  Patients will be contacted 
approximately 30 days post [18F]Flutemetamol scanning to collect information from 
the patient regarding pregnancy status. 
A follow-up telephone call will be made to each participant within 1 day following 
their imaging scan with [18F]Flutemetamol.  If the participant cannot be contacted at 1 
day post-scanning, then we will continue trying to contact them for up to 7 days post-
scanning. 

PI: Jeffrey Yap, PhD  
 
     Page 64 of 73 
Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
Version Date: 03/21/2024 
 
 
University of Utah IRB  
Document Version:  010312 
4 
The research MRI study and neuropsychological testing can be completed depending 
on staff availability and can be done before, after, or in between PET/CT imaging 
sessions. 
 
 
Research MRI study 
The research MRI study will include the following imaging sequences/studies. This is our 
current clinical brain tumor imaging protocol.  
Scout 
T1–weighted SE (pre injection) 
T2  
FLAIR;  
Dynamic contrast enhanced images with associated T1 mapping 
Diffusion- weighted imaging 
Post T1–weighted SE 
 
PET Imaging Visits 1 & 2:   
Imaging of the PET tracers will be performed on two separate days with FDG imaging 
occurring on one day and [18F]Flutemetamol occurring on another day. The imaging will be 
performed on separate days depending on scheduling with the cyclotron. The days of 
imaging will be scheduled according to scanner and cyclotron availability, and all days of 
imaging will be obtained within six weeks of each other. 
 
 

PI: Jeffrey Yap, PhD  
 
     Page 65 of 73 
Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
Version Date: 03/21/2024 
 
 
University of Utah IRB  
Document Version:  010312 
APPENDIX E: [18F]Flutemetamol Patient Adverse Event Questionnaire  
 
Completed at conclusion of [18F]Flutemetamol infusion.  
 
Subject Name and MRN: _________________________________   Subject Study ID (if enrolled) _____________     
                
Projected Study Start Date_______________   Referring MD____________________________________________ 
 
Possible Adverse Event 
Y =Yes      Comment on possible AE 
N = No 
Body as a Whole: 
Pain (Abdominal) 
 
Pain (Chest/Breast) 
 
Pain (Other site) 
 
Fever 
 
Injection site reaction 
 
 
Cardiovascular System: 
Vasodilation (flushing) 
 
 
Digestive System: 
Nausea 
 
Diarrhea 
 
Vomiting 
 
 
Respiratory System: 
Dyspnea (Shortness of breath) 
 
 
Skin and Appendages: 
Rash 
 
Pruritus (Itching) 
 
Urticaria (Hives) 
 
Sweating  
 
Cyanosis (discoloration of fingers/toes) 
 
 
Central Nervous System 
 
Visual disturbances 
 
Numbness of feet 
 
Numbness of fingers/hands 
 
Weakness of feet 
 
Weakness of fingers 
 
Burning sensation in feet 
 
Burning sensation of fingers 
 
 
Performed by ______________________        Date _______________ 
Time ______________ 
 
PI Oversight ________________________      Date__________________Time______________ 

PI: Jeffrey Yap, PhD  
 
     Page 66 of 73 
Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
Version Date: 03/21/2024 
 
 
University of Utah IRB  
Document Version:  010312 
APPENDIX F:  NCI Common Toxicity Criteria 
 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf 
 
 
 

PI: Jeffrey Yap, PhD  
 
     Page 67 of 73 
Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
Version Date: 03/21/2024 
 
 
University of Utah IRB  
Document Version:  010312 
APPENDIX G:  GE Healthcare Pregnancy Reporting Form 
 
GE HEALTHCARE  
Pregnancy Reporting Form 
ISS NO. 
SUBJECT NO. 
Investigational 
Product 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Please report to GEHC MDx all reported pregnancies that occur within 30 days of 
exposure to the investigational product. 
Please send this form within 24 hours of a positive pregnancy test, to the GEHC MDx 
Pharmacovigilance Department,  
In the Americas : Fax: 609-514-6575  
Rest of World: Fax: + 47 23 18 60 29 
 
 
 
Date of last menstrual period (first day): 
 
 
 
 
 
 
2 0  
 
 
 
 
D 
D 
M 
M 
M 
Y 
Y 
Y 
Y 
 
 
 
Date of verified pregnancy: 
 
 
 
 
 
 
2 0  
 
 
 
 
D 
D 
M 
M 
M 
Y 
Y 
Y 
Y 
 
 
 
Date of expected birth: 
 
 
 
 
 
 
2 0  
 
 
 
 
D 
D 
M 
M 
M 
Y 
Y 
Y 
Y 
 
 
Has the pregnancy proceeded normally so far? 
 Yes 
 No 
If No, please specify:__________________________________________________________ 
___________________________________________________________________________ 
___________________________________________________________________________ 
 
 
 
Investigator’s Signature: 
_______________________________ 
 
 
 
 
 
 
2 0  
 
 
 
 
D 
D 
M 
M 
M 
Y 
Y 
Y 
Y 
 

PI: Jeffrey Yap, PhD  
 
     Page 68 of 73 
Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
Version Date: 03/21/2024 
 
 
University of Utah IRB  
Document Version:  010312 
APPENDIX H:  GE Healthcare SAE Reporting Form 

PI: Jeffrey Yap, PhD  
 
     Page 69 of 73 
Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
Version Date: 03/21/2024 
 
 
University of Utah IRB  
Document Version:  010312 
 

PI: Jeffrey Yap, PhD  
 
     Page 70 of 73 
Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
Version Date: 03/21/2024 
 
 
University of Utah IRB  
Document Version:  010312 
 
 
Sponsor-Investigator Name: 
Initial Report 
 
Follow-up 
Report 
 
Blinded trial - Investigational Products tested: 
Open trial - Investigational Product administered:  
ISS ID number: 
 
 
 
 
Subject Number 
 
 
 
 
 
 
 
 
Gender: 
Female 
Male 
 
     
Subject age: 
Height /units: 
Weight /units: 
Race
: 
Caucasian 
 
Black 
 
Hispanic 
 Asian 
 
Other 
  (specify): 
_________________ 
Therapy start date/time:   ____/_____/_____; 
____:____ 
 
 
 
dd/mmm/yyyy; hh:mm (military time) 
Therapy end date/time:  
____/_____/_____; ____:____ 
 
 
 
dd/mmm/yyyy; hh:mm 
(military time) 
Dose/units: 
 
Route of 
administration: 
 
Type of 
examination: 
if applicable 
 
Indication for 
examination: 
if applicable 
 
Event term: 
Onset date/time:               ____/_____/_____; 
____:____ 
 
 
 
dd/mmm/yyyy; hh:mm (military time) 
Resolution date/time:     
____/_____/_____; ____:____ 
 
 
 
dd/mmm/yyyy; hh:mm (military 
time) 
Relationship to Investigational Product: 
1 = Before IP admin 
2 = After IP admin - relationship to IP NOT Suspected 
3 = After IP admin - relationship to IP IS Suspected 
Intensity: 
1 = Mild 
2 = Moderate 
3 = Severe 
Outcome: 
1 = Resolved 
2 = Not resolved 
3 = Death 
Which of the following criteria were met (check all that apply): 
Death 
  Life-threatening 
 Hospitalization 
  
Disability 
 
Congenital anomaly 
 
 
Other important medical condition 
 describe why 
Did event abate/stop when IP stopped? 
Yes 
 
 
No 
 
Not applicable 
 
Did event reappear/worsen when IP restarted? 
Yes 
 
 
No 
 
Not applicable 
 
Death date/time:                ____/_____/_____; 
____:____ 
 
 
 
dd/mmm/yyyy; hh:mm (military time) 
Cause(s): 
Was the subject withdrawn due to this 
event? 
Yes 
  
No 
 

PI: Jeffrey Yap, PhD  
 
     Page 71 of 73 
Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
Version Date: 03/21/2024 
 
 
University of Utah IRB  
Document Version:  010312 
Relevant medical/surgical history: 
 
 
Describe course of event: 
 
 
Continuation page number:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor-Investigator signature: _____________________________________ 
Date:_________________ 
 
 

PI: Jeffrey Yap, PhD  
 
     Page 72 of 73 
Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
Version Date: 03/21/2024 
 
 
University of Utah IRB  
Document Version:  010312 
APPENDIX I:  GE Healthcare Supplemental Safety Reporting Form 

PI: Jeffrey Yap, PhD  
 
     Page 73 of 73 
Title: Amyloid Plaque Deposition in Chemotherapy-Induced Cognitive Impairment 
IND Number:  [18F]Flutemetamol – IND # 109,760, FDG – IND # 113,858 
Previous Version Date: 01/11/2021 
Version Date: 03/21/2024 
 
 
University of Utah IRB  
Document Version:  010312