Pilot Study of 11C-Choline (11C-CH) PET in Assessing Post-treatment True Tumor Progression From Pseudo-progression in High-grade Gliomas
Phase: NA
Conditions: Brain Cancer
Sponsor: Memorial Sloan Kettering Cancer Center

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-676 A(6) 
Approval date: 11-Sep-2019 
Page 1 of 23 
 
 
 
 
Pilot Study of 11C-Choline  (11C-CH) PET in assessing  post-treatment  true 
tumor progression  from pseudo-progression  in high-grade  gliomas. 
PROTOCOL FACE PAGE FOR 
MSK NON THERAPEUTIC PROTOCOL 
 
 
Principal Investigator/Department: 
Ronald Blasberg, MD 
Neurology 
Co-Principal  Investigator(s)/Department: 
Heiko Schoder, MD 
Heiko Schoder, MD 
Investigator(s)/Department: 
Cameron Brennan, MD 
Philip Gutin, MD 
Mark Dunphy, DO 
Jason Lewis, PhD 
Katherine Panageas, DrPH 
Marc Rosenblum, MD 
Allison Hyde, RN 
Dana Bossert, RN 
Milagros Gordillo, NP 
Mimma Errante, NP 
Neurosurgery 
Neurosurgery 
Molecular Imaging and Therapy 
Services (MITS) 
Radiology/Radiochemistry  and 
Imaging Sciences Service 
Biostatistics 
Pathology 
Nursing 
Nursing 
Nursing 
Nursing 
Consenting  Professional(s)/Department: 
Lisa M. DeAngelis, MD 
Eli L. Diamond MD 
Thomas Kaley, MD 
Ingo Mellinghoff,  MD 
Elena Pentsova, MD 
Christian Grommes, MD 
Craig Nolan, MD 
Igor Gavrilovic, MD 
Adrienne Boire, MD PhD 
Jacqueline Stone, MD 
Bianca Santomasso, MD PhD 
Richard Phillips, MD PhD 
Andrew Lin, MD 
Anna Piotrowski, MD 
Alexandra Miller, MD PhD 
Synphen Wu, MD PhD 
Rachna Malani, MD 
Lauren Schaff, MD 
Milagros Gordillo, NP 
Mimma Errante, NP 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology 
Nursing 
Nursing 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
 
OneMSK  Sites 
Manhattan 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-676 A(6) 
Approval date: 11-Sep-2019 
Page 2 of 23 
 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ....................................................................... 4 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ................................................................................ 5 
3.0 
BACKGROUND AND RATIONALE ..................................................................................... 5 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................................. 10 
4.1 
Design................................................................................................................................. 10 
4.2 
Intervention .............................................................................................................................. 10 
5.0 
CRITERIA FOR SUBJECT ELIGIBILITY ............................................................................... 10 
5.1 
Subject Inclusion Criteria ..................................................................................................... 10 
5.2 
Subject Exclusion Criteria ................................................................................................... 11 
6.0 
RECRUITMENT PLAN .................................................................................................................... 11 
7.0 
ASSESSMENT/EVALUATION PLAN ................................................................................. 12 
8.0 
TOXICITIES/SIDE EFFECTS .................................................................................................... 14 
9.0 
PRIMARY OUTCOMES ..................................................................................................... 15 
10.0 
CRITERIA FOR REMOVAL FROM STUDY ....................................................................... 15 
11.0 
BIOSTATISTICS ............................................................................................................... 15 
12.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
17 
12.1 
Research Participant Registration ....................................................................................... 17 
12.2 
Randomization .................................................................................................................... 17 
13.0 
DAT A M ANAGEMENT ISSUES ........................................................................................ 17 
13.1 
Quality Assurance............................................................................................................... 17 
13.2 
Data and Safety Monitoring .................................................................................................... 17 
14.0 
PROTECTION OF HUMAN SUBJECTS ............................................................................ 18 
14.1 
Privacy ................................................................................................................................ 19 
14.2 
Serious Adverse Event (SAE) Reporting................................................................................ 19 
15.0 
INFORMED CONSENT PROCEDURES................................................................................... 20 
16.0 
REFERENCES ....................................................................................................................... 21 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-676 A(6) 
Approval date: 11-Sep-2019 
Page 3 of 23 
 
 
 
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
This is a pilot study evaluating the ability of 11C-choline (11C-CH) PET imaging to evaluate 
11C-CH distribution in the head and to distinguish pseudo-progression from true tumor 
progression in high-grade gliomas treated with radiation.   Distinguishing true tumor progression 
from pseudo-progression in gliomas remains a challenge with conventional gadolinium-enhanced 
MRI and FDG PET.  Radiographic and FDG PET changes in pseudo-progression are often 
indistinguishable from those related to true tumor progression. Thus,  current advanced imaging 
techniques are not sufficient in distinguishing these two processes.  With a more accurate and an 
earlier understanding of the pathology of evolving radiographic changes following treatment of 
high-grade gliomas, more effective treatment decisions could be made earlier on in the course of 
treatment and may lead to improved patient outcomes. 
 
Here we propose to study the biodistribution of 11C-CH using PET imaging and to obtain 
pilot data as to whether 11C-CHcan differentiate lesions primarily composed of recurrent tumor 
versus inflammation associated with treatment.  11C-CH PET is a nuclear imaging modality that 
has been used for the detection of proliferating cells as opposed to inflammation.7    This is 
particularly relevant to brain tumors, where 11C-CH has a very low background uptake, 
contributing to high sensitivity for identifying neoplasia. 
 
In this small plot study of 6 patients, we seek to determine the uptake and biodistribution 
of 11C-CH with the purpose of correlating SUV measures with evolving MRI findings consistent 
with a diagnosis of tumor progression versus pseudoprogression. 
Our central hypothesis is that 11C-CH PET imaging will delineate those lesions with 
a large fraction of tumor cells, consistent with true progression, from those with 
inflammatory cells as seen in pseudo-progression.  This pilot study will not be considered 
definitive, but rather will be used to gather preliminary data in support of a larger, 
definitive study. 
 
The 11C-CH will be used in this trial, strictly in concordance with the requirements of the 
Radioactive Drug Research Committee (RDRC). The RDRC permits the study of up to 30 human 
subjects with a research radiotracer prior to an IND application provided: (1) the radiotracer is not 
a first in man study, (2) the agent is administered at doses below that which will produce a 
pharmacologic effect and (3) the projected radiation dose falls within defined limits; namely <3cGy 
for eyes, bone marrow and testes per injection and <5 cGy per annum; for all other organs <5cGy 
per injection or <15 cGy per annum.  This trial will investigate the distribution of a research agent. 
The trial is intended to discover where the agent distributes within the head (RDRC justification), 
as well as address objectives 1 and 2. The individual patient results from this study will not be 
used for disease diagnosis or to assess treatment response or to change treatment decisions. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-676 A(6) 
Approval date: 11-Sep-2019 
Page 4 of 23 
 
 
~4 expected to have a 
11 
ne gative  C-CH PET 
scan consistent with 
“pseudo-progression” 
 
 
 
Study Scheme: 
 
 
 
 
 
 
 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
2.1 
Primary Objective: 
 
(a) To determine the distribution of 11C-CH in high-grade glioma lesions with MRI findings 
concerning for pseudoprogression vs true tumor  progression following radiotherapy 
(with or without concurrent therapy). 
(b) To investigate the correlation between 11C-CH SUV measures and MRI follow-up 
outcomes in patients with high-grade glioma lesions with changes concerning for 
pseudoprogression vs true tumor progression following treatment with radiation (with 
or without concurrent therapy). 
 
Hypothesis: 11C-CH PET imaging has high uptake in “true tumor progression” (recurrent tumor) 
relative to evolving treatment related inflammatory changes following radiation and/or 
chemotherapy  (“pseudo-progression”). 
 
 
3.0     BACKGROUND AND RATIONALE 
W hat is post-treatment gliom a “ps eudo-progres s ion”? Glioma pseudo-progression occurs in 28- 
66% of all glioblastoma (GBM) patients undergoing chemoradiation and typically presents as an 
increased area of contrast enhancement and surrounding T2/FLAIR hyperintense signal.[1] These 
findings are often indistinguishable from those related to true progression of tumor on standard 
MRI. The radiographic changes of pseudo-progression range from mild to dramatic, may or may 
not result in neurologic symptoms, and typically occur within 3-6 months of standard combined 
radiation and temozolomide therapy.[1, 2] Patients with tumors harboring promoter methylation of 
the repair enzyme O-6-methyl guanine DNA methyltransferase (MGMT) appear to be at greater 
risk for pseudo-progression, with up to 91% (21 of 23 patients) of such patients developing early 
radiographic changes in one study.[3] The pathophysiology of glioma pseudo-progression is not 
fully  understood.  It  is  most  likely  induced  by  a  pronounced  local  tissue  reaction  with  an 
40-60% develop 
post-treatment 
w orsening of their 
contrast MRI 
Patient Base 
~300+ high- 
grade gliomas 
treated w ith 
single or 
combined 
XRT + Chemo 
at MSKCC 
40-60% not eligible 
Standard long- 
term monitoring 
and therapy to 
determine a 
diagnosis of 
“pseudo- 
progression” vs. 
“true progression” 
11 
C-CH PET 
scan 
~2 expected to have a 
11 
positive  C-CH PET 
scan consistent with 
“true progression” 
Enroll 
in   study 
(N=6) 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-676 A(6) 
Approval date: 11-Sep-2019 
Page 5 of 23 
 
 
 
 
inflammatory component, edema, and abnormal vessel permeability causing new or increased 
contrast enhancement on MR imaging examinations. Most important, there may be an association 
between the incidence of pseudo-progression and increased survival, suggesting pseudo- 
progression represents an active “inflammatory” response against the tumor.[3] 
 W hy is it c linic ally im portant to diff erentiat e bet ween “true progres s ion” and “ps eudo-pro gres s ion”. 
Differentiating between true progression and pseudo-progression provides critical information to 
guide patient management decisions. In patients with pseudo-progression, the imaging findings 
represent treatment-related inflammatory changes secondary to a robust response to therapy and 
continued treatment is appropriate and beneficial. For patients in whom pseudo-progression is 
suspected, continued therapy with close monitoring is recommended as the  contrast 
enhancement will typically remain stable or improve.[4] For patients who are symptomatic from a 
growing lesion in an eloquent portion of the brain, observation is not feasible, and the prompt 
diagnosis of tumor progression versus pseudo-progression is imperative to ameliorate  and 
prevent further disability. Tumor recurrence needs to be managed more aggressively to prevent 
growth, and early identification of recurrence could impact a patient’s overall  prognosis  and 
survival. An accurate assessment of treatment response is also fundamental in clinical trials and 
is becoming increasingly relevant with the growing interest in immunotherapies for high-grade 
gliomas. 
Diagnosis of pseudo-progression. Distinguishing pseudo-progression from tumor progression 
radiographically remains a challenge. Conventional gadolinium enhanced MRI is currently the 
standard method of evaluating response to chemoradiation, and the Macdonald Criteria are the 
most widely used response assessment guidelines for high-grade gliomas.[5] These are based on 
2D tumor measurements on MRI, in conjunction with clinical assessment, and corticosteroid dose. 
The Macdonald Criteria define tumor progression as any increase of >25% in the size of the 
contrast-enhancing lesion, but are limited as only the enhancing portion of the tumor is measured. 
The revised RANO criteria attempt to address this and account for the nonenhancing component 
of the tumor in assessing response.[6] They are also more stringent in defining true progression 
within 12 weeks after radiation only with pathologic confirmation or with the presence of a new 
lesion outside the radiation field. Comparing these two criteria, it is clear that tumor progression is 
“over-diagnosed” using the Macdonald criteria, resulting in a subsequent diagnosis of pseudo- 
progression of 24% for Macdonald and 13% for RANO criteria.[7] Even with the modified criteria, 
current imaging techniques are not sufficient in reliably distinguishing tumor progression from 
treatment related changes. Although limited retrospective data suggest perfusion MR may be 
useful, its sensitivity is comparable to FDG-PET, which is low or disputed in some studies.[4, 8- 
12] Furthermore, most studies utilize the first MRI following chemoradiation to determine 
radiographic progression, limiting our understanding of the timeline of treatment-related 
inflammatory changes. Indeed, some investigators have considered pseudo-progression up to 6 
months post-radiation, with one study demonstrating 33% of pseudoprogression cases occurring 
3-6 months following treatment initiation [13], highlighting the poorly defined measures used in the 
diagnosis of this entity.[13-15] 
Choline Metabolism: Choline is a quaternary (hydrophilic) amine and is an “essential” nutrient that 
must be obtained from the diet. Choline is predominantly utilized for the synthesis of essential 
lipid components of cell membranes (e.g., phosphatidylcholine (PtdylC) and sphingomyelin), the 
production 
of 
potent 
lipid 
mediators 
(such 
as 
platelet-activating 
factor 
and 
lysophosphatidylcholine), and for the synthesis of the cholinergic neurotransmitter acetylcholine 
(ACh). PtdylC is the most important metabolite of choline and accounts for approximately one-half 
of total membrane lipid content and is the largest fraction of choline metabolites.[16] 
Choline is initially transported into the cell and then phosphorylated by choline kinase, forming 
phosphocholine (PCho). Choline transporters and choline kinase are frequently overexpressed in 
malignancy.[17-23] PCho is  readily detected by  31P  magnetic  resonance spectroscopy (MRS), 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-676 A(6) 
Approval date: 11-Sep-2019 
Page 6 of 23 
 
 
Mean, ± SD; *a 
 
 
and elevated levels of “choline” (C-NH3)3 moieties are detected by 1H MRS. These measures 
have been used as surrogate markers for tumors, but elevated levels are also found in many 
rapidly dividing cells. MRS imaging of elevated choline has been shown in numerous studies of 
breast, brain, and prostate tumors and is a marker of malignancy.[24-29] 
Fluorocholine imaging: 18F-FCH has demonstrated utility for imaging a variety of neoplasms, 
including those of the  breast, prostate, liver and brain.  Imaging metastatic  and primary brain 
tumors with 18F-FCH has also been demonstrated (Figs. 1-3, Table 1). The results summarized in 
Table  1  demonstrate  that  18F-FCH uptake  in 
primary brain tumors is very high, and most 
important, that uptake is very low in “benign” 
brain inflammatory lesions (e.g. demylinating 
disease and radiation necrosis), as well as in 
normal brain tissue.[30] 
Table 1. 
18F-FCholine  PET data [30] 
 
ll pairwise comparisons were significant. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1. Glioblastoma: Contrast enhanced MRI (left) and 18F- 
FCholine PET (right). Note visualization of an infiltrating portion of 
the tumor on the FCH PET image (arrow), that is not seen on the 
contrast enhanced MRI. Also note the low background acti vity in 
non-tumor  normal brain regions  [20]. 
 
 
Comparison to 11C-Choline: The imaging characteristics (e.g., tumor/brain) of 18F-FCH and 11C- 
Choline are similar (Fig. 2). Although there are advantages to 18F-FCH, including the longer 
physical half-time of 18F (t1/2=110 min) compared to 11C (t1/2=20 min) and the slightly greater in 
vivo stability of 18F-FCH[31, 32], radiation exposure (dosimetry) is significantly less with 11C- 
Choline (approximately 1/5 that of 18F-FCH), allowing repetitive 11C-Choline studies. In addition, 
11C-CH is produced frequently (several times each week) for prostate cancer imaging studies at 
MSKCC. Furthermore, an IND for 11C-CH PET imaging has been approved for these studies. 
Parameter 
High-grade 
Gliomas 
(n-13) 
Benign 
Lesions 
(n-9) 
P Value 
SUVmax* 
1.89±0.78 
0.59±0.31 <.0001 
White matter SUV 
0.40±0.13 
0.46±0.20 .58 
Lesion/Brain Ratio* 5.15±2.51 
1.28±0.32 <.0001 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-676 A(6) 
Approval date: 11-Sep-2019 
Page 7 of 23 
 
 
 
 
 
 
 
Figure  2. 
18 
F-  and 
11 
C-Choline  PET scans  were  similar  at  5  and  20 
minutes post-injection in a glioblastoma. However,  the Tumor/Brain ratio 
(T/B)  of 
18 
11 
F-FCholine  increased  with  time,  whereas  the  ratio  of 
C- 
18 
Choline was constant.   As a consequence, the T/B ratio of 
F-FCholine 
at 20 minutes post-injection was higher, ranging from 13.2 to 21.1 (16.2 
+/- 2.6, seven cases) in glioblastoma  [31]. 
 
Comparison to 18F-FDG. FDG is avidly accumulated by many tumor cells and is widely used to 
stage many malignancies. FDG has also been used in the past in an attempt to differentiate tumor 
recurrence from radiation necrosis. However, FDG accumulates avidly in inflammatory lesions, 
where white blood cells and macrophages have high rates of glycolysis. Non-neoplastic 
applications of FDG-PET were recently reviewed in 16 articles published in the Annals of the New 
York Academy of Sciences.[33] In fact, there are many reports where FDG-avid brain lesions 
have subsequently been shown to be non-malignant inflammatory lesions, including radiation 
necrosis with an inflammatory infiltrate. [17-23] Reports on the sensitivity and specificity of FDG- 
PET to distinguish recurrent tumor from radiation necrosis, involving 363 patients in 12 studies 
varied widely (9 reviewed in reference [34], [11, 35]). Since 1988, sensitivity and specificity values 
ranged from 65-86% and 22-94%, respectively, although a recent small (n=25) dual phase study 
reported values of 90-95% and 95-100% respectively.[11, 34-36] Thus, FDG-PET is inconsistent 
in identifying radiation necrosis and is less frequently used in current clinical management. 
Furthermore, the background level of FDG in normal brain tissue is high, which further minimizes 
sensitivity and complicates its ability to distinguish active, progressive brain tumors from other 
inflammatory brain diseases. 
 
Comparison to 18F-FLT. Comparing 18F-FCH to 18F-fluorothymidine (FLT) (and amino acid uptake) 
may be more appropriate, because both tracers have relatively low brain background. However, 
there are no published head-to-head 
18F-FCH and 
18F-FLT (or radiolabeled amino acid) 
comparisons for primary or metastatic brain tumors. A comparison can be made between two 
different studies involving patients with high-grade gliomas. The FLT SUVmax and LNR (lesion-to- 
normal brain ratio) values (1.33 ± 0.75 and 3.54 ± 1.03, respectively) were slightly  lower 
compared to those for 18F-FCH.[30,37] These differences are small and were not statistically 
significant. No comparable SUVmax or LNR values for FLT uptake in brain metastases or radiation 
necrosis have been reported. FLT has been reported to have low uptake in inflammatory lesions, 
and FLT is consistently better than FDG in distinguishing tumor from inflammation.[38-40] 
However, FLT uptake in BCG-induced granulomas was comparable to that in KDH-8 hepatomas 
(2.2±0.5 vs. 2.6±0.8 lesion/blood). FLT uptake in turpentine-induced inflammation was slightly 
lower (1.4±0.2 lesion/blood) than that in granulomas, but significantly above baseline.[40] One 
recent abstract reports a comparison of FLT- and FDG-PET in differentiating recurrent tumor from 
radiation necrosis in 15 patients with primary brain tumors.[41] Sensitivity/specificity FLT Kimax 
was 91/75% (p=0.0071), whereas sensitivity/specificity for FDG SUVmax was 82/100% (p=0.0016); 
visual distinction between recurrent tumor and radiation necrosis was statistically significant for 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-676 A(6) 
Approval date: 11-Sep-2019 
Page 8 of 23 
 
 
 
 
FDG (p=.007), but not for FLT (p=.066). These differences reflect some inconsistency in the 
published literature. 
 
Comparison to radiolabeled amino acids. Similar to FLT, many radiolabeled amino acids (11C- 
methionine and 18F-fluoroethyltyrosine [FET]) have relatively high tumor and low brain uptake. 
However, normal brain uptake of the amino acids is higher than that of 18F-FCH, whereas tumor 
uptake of 11C-Choline and 18F-FCH is greater than that of 11C-methionine and other  amino 
acids.[3] Several relevant studies have been reported.[42-47] One recent study of 29 patients (33 
lesions) using 11C-methionine to distinguish brain tumor recurrence from radiation necrosis,[43] 
reports a SUVmax sensitivity, specificity, and accuracy of 68.2% (15/22), 72.7% (8/11) and 69.7% 
(23/33), respectively.[43] These values reflect those reported in other amino acid imaging 
studies.[42, 44-47] 
 
Comparison to MRI perfusion. MRI perfusion provides physiologic information about brain tissue 
biology, allowing the in vivo measurement of increased tumor microvascularity and permeability. 
There is growing evidence that MRI perfusion can improve the diagnosis of bra in tumors over 
conventional imaging alone. DCE MRI perfusion is a T1 technique with excellent spatial resolution 
and is relatively insensitive to susceptibility artifacts due to hemorrhage and bone/air interfaces. 
DCE MRI perfusion provides measurements of plasma volume and Ktrans. Although small 
retrospective and prospective studies have suggested a role for MRI perfusion in distinguishing 
tumor progression from treatment related changes, there still remains considerable overlap 
between these two disease entities.[4, 8-10, 48, 49] There is an open protocol at MSKCC (IRB 
12-067) comparing MRI perfusion and FDG-PET/CT to distinguish between radiation injury and 
tumor progression. 
 
Comparison to spectroscopy (MRS). MRS in combination with standard MRI sequences is clearly 
better than MRI alone in distinguishing treatment related changes from recurrent tumor. Using 1H 
MRS, resonances from choline (C-NH3)3 moieties (Cho), creatine+phosphocreatine (Cr), N-acetyl- 
aspartate (NAA), lactate (Lac), and free fatty acids can be resolved well enough to assist in the 
diagnosis under routine conditions, and PCho is readily detected by 31P MRS. These measures 
and combination of measures (e.g., Cho/Cr ratio) have been used as surrogate markers of brain, 
breast, prostate and other tumors in numerous studies,[24-29] and are considered to be a marker 
of malignancy. In contrast, other combinations (e.g., Lac/Ch) have been used as a marker of 
necrosis. Small studies have been reported in primary brain tumors.[49-54] However, no large 
comprehensive efficacy studies have been performed. 
Preliminary Data. This proposal is based on observations that gliomas have a much higher uptake 
of 18F-FCH and 11C-CH than non-proliferative brain lesions and surrounding normal brain tissue, 
thus providing a clear distinction between the two processes (Table 1).[30] MSK has recently 
been funded to study whether 18F-FCH PET imaging can distinguish between post-stereotactic 
radiosurgery (post-SRS) induced radionecrosis versus recurrent tumor (R21; IRB-13-199). The 
results have been very encouraging (see Fig. 3). 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-676 A(6) 
Approval date: 11-Sep-2019 
Page 9 of 23 
 
 
 
 
 
 
Figure 3.  A patient at MSKCC with an evolving brain lesion following stereotactic radiosurgery for 
a lef t f rontal lobe lung adenocarcinoma metastasis. The patient was scheduled for surgical 
resection based on clinical grounds, prior to enrollment in the 18F-FCholine  PET study (protocol 
13-199). Panel A shows foci of high 18F-FCholine uptake in the lesion. Panel B shows some 
irregular 18F-FDG  uptake around the lesion (the level of uptake is between cortex and white 
matter), which is difficult to interpret. The official reading attributed the f indings to radiation 
necrosis and less likely viable tumor. Panel C shows the lesion with irregular contrast 
enhancement. Panel D shows a FLAIR signal well beyond the margins of contrast enhancement, 
suggesting the presence of significant brain edema. The official p atho log ic d iag no sis of tissue 
removed at time of surgery was consistent with metastatic adenocarcinoma. 
18F-FCholine 
18F-FDG 
Contrast MRI 
FLAIR MRI 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-676 A(6) 
Approval date: 11-Sep-2019 
Page 10 of 23 
 
 
 
 
Investigational Use of 11C-CH. This study involves the use of an investigational radiotracer 11C- 
CH that will be performed under the MSKCC Radioactive Drug Research Council (RDRC) and, 
therefore, will comply with the requirements  of the committee  as  specified on page 4 of the 
protocol. The purpose of this research study is to discover where the agent distributes within the 
head (RDRC justification), and explore whether 11C-CH can distinguish between true tumor 
progression and psuedoprogression and evaluate the biodistribution of 11C-CH in these lesions. 
No clinical decisions will be made on the basis of the 11C-CH PET scan. A total of 6 patients will 
be enrolled on this study. The administered activity of 11C-CH has been determined to ensure that 
the radiation dosimetry falls below the limits required by RDRC. 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.2 
Design 
This is a non-therapeutic pilot study performing 11C-CH PET imaging of patients with high-grade 
gliomas who develop MRI findings consistent with recurrent tumor and/or pseudo-progression 
within 24 weeks after completion of treatment with radiation (with or without concurrent therapy). 
The objective of this trial is to correlate 11C-CH PET SUV measures with MRI follow-up  
outcomes. Each patient will be followed up for at least 11 months after completion of the PET 
scan to confirm MRI changes as representing pseudoprogression or true tumor progression. This 
study will not be used to make a clinical diagnosis or to change treatment decisions. Six patients 
will be enrolled on this study over a 1 year period. 
4.3 
Intervention 
 
This study will enroll patients with a histologically confirmed diagnosis of a high-grade glioma. 
Eligible patients must have undergone standard radiation (typically 60Gy in 30 fractions), with or 
without concurrent drug therapy, and have MRI findings consistent with tumor progression and/or 
pseudoprogression within 24 weeks after completion of radiation. Eligible patients will undergo  
an 11C-CH PET study within 2 weeks of the standard of care MRI that shows changes concerning 
for tumor progression vs. pseudoprogression. All patients will then be followed with surveillance 
brain MRI with and without contrast as per standard of care for a period of 11 months, to assess 
further progression or stabilization of the lesion. Initial MRI changes are considered to represent 
pseudoprogression/treatment related changes if the lesion stabilizes or becomes smaller without 
a change in tumor-related therapy. Otherwise, it will be considered a recurrence should there be 
progessive radiographic changes. 
 
 
5.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
Describe the characteristics of the subject population. 
 
5.1 
Subject Inclusion Criteria 
 
o Age ≥ 18 years 
o Patient is able to provide written informed consent prior to study registration 
o Histologically-confirmed high-grade glioma 
o Completion of treatment with standard radiation (with or without concurrent 
therapy). 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-676 A(6) 
Approval date: 11-Sep-2019 
Page 11 of 23 
 
 
 
 
o Standard gadolinium-enhanced MRI changes that are considered indeterminate for 
tumor progression vs. treatment-related changes by the neuroradiologist or 
clinician within 24 weeks of completion of radiation. 
 
5.2 
Subject Exclusion Criteria 
 
▪ 
Inability to undergo or cooperate with an MRI or PET scan (e.g., claustrophobia, metal 
implant) 
▪ 
Renal insufficiency with recent (<3 month old) creatinine > 2.0 mg/dL 
▪ 
Pregnant or nursing female 
 
 
 
6.0 
RECRUITMENT PLAN 
 
Patients for this study will be recruited by physicians from the Departments of Neurology. 
Approximately 300 patients with high grade gliomas treated with radiation with or without 
concurrent therapy are seen a year.  Approximately 30-40% will develop progressive radiographic 
changes on MRI brain concerning for tumor progression, typically within the first 24 weeks 
following completion of treatment with radiation.  Of those patients approximately 30-40% with 
have pseudoprogression as opposed to true tumor progression. A small percentage of these 
patients will require surgical intervention for symptom management.  We expect to enroll 6 
patients over a one year period who require surgical resection of the lesion for management of 
progressive symptoms or if there is clinical need to establish a histologic diagnosis. Additional 
patients may be enrolled to replace a previously enrolled patient should surgical resection not 
yield adequate tissue to complete the histopathologic metrics required for the second objective of 
the study. 
All adult patients ≥18 years are eligible for participation regardless of sex or race. Every effort will 
be made to encourage eligible women and minorities to enroll in this study. Prior to study entry, 
the study staff will explain to each potential subject the research objectives, risks and benefits of 
study participation, alternative treatments available, and the subjects’ rights and responsibilities. If 
the patient agrees to participate in the study, informed consent will be obtained by a consenting 
individual on the study. All patients must sign written informed consent prior to being registered on 
this protocol. 
The principal investigator may also screen the medical records of patients with whom they do not 
have a treatment relationship for the limited purpose of identifying patients who would be eligible 
to enroll in the study and to record appropriate contact information in order to approach these 
patients regarding the possibility of enrolling in the study. 
During the initial conversation between the investigator/research staff and the patient, the patient 
may be asked to provide certain health information that is necessary to the recruitment and 
enrollment process.  The investigator/research staff may also review portions of their medical 
records at MSKCC in order to further assess eligibility.  They will use the information provided by 
the patient and/or medical record to confirm that the patient is eligible and to contact the patient 
regarding study enrollment.  If the patient turns out to be ineligible for the research study, the 
research staff will destroy all information collected on the patient during the initial conversation 
and medical records review, except for any information that must be maintained for screening log 
purposes. 
In most cases, the initial contact with the prospective subject will be conducted either by the 
treatment team, investigator or the research staff working in consultation with the treatment team. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-676 A(6) 
Approval date: 11-Sep-2019 
Page 12 of 23 
 
 
 
 
The recruitment process outlined presents no more than minimal risk to the privacy of the patients 
who are screened and minimal PHI will be maintained as part of a screening log. 
 
 
7.0 
ASSESSMENT/EVALUATION PLAN 
7.1 
PRE-IMAGING EVALUATION 
The following tests and procedures need to be performed within 14 days of study registration 
unless stated otherwise: 
• 
History and Physical exam, including Neurologic exam 
• 
MRI brain with/without contrast with findings consistent with radiographic progression 
versus pseudoprogression. 
• 
Laboratory studies obtained as part of standard clinical care 
o Serum creatinine 
o Serum pregnancy test (women of childbearing potential) within 7 days of the 
first PET scan 
 
7.2 
11C-CH PET imaging and injection 
All patients will undergo a single head PET/CT scan, measuring 11C-CHradioactivity.  This 
PET scan will be performed within 2 weeks of the brain MRI that demonstrates 
radiographic findings concerning for true tumor progression vs pseudoprogression. 
Various metrics derived from this data (including simple threshold SUV values) will be 
assessed for their ability to differentiate between pseudoprogression and recurrent tumor 
as confirmed by the evolution of the lesion on subsequent standard of care surveillance 
MRIs. 
 
Radiographic changes will be defined as progression rather than pseudoprogression 
within that 24 week window per modified RANO criteria.  However, unlike the RANO 
criteria, the protocol will allow for a broader window of 24 weeks after completion of 
radiation instead of 12 weeks to maximize enrollment. Progression can only be defined 
using diagnostic imaging less than 24 weeks after completion of radiation if there is new 
enhancement outside the radiation field (beyond the high-dose region or 80% isodose 
line) or if there is unequivocal evidence of viable tumor or histopathologic sampling (ie, 
>70% tumor cell nuclei in areas, high or progressive increase in MIB-proliferation  index 
compared with prior tissue, or evidence for histologic progression or increased anaplasia 
in tumor).  Given the difficulty of differentiating  true progression from pseudoprogression, 
clinical decline alone, in the absence of radiographic or histologic confirmation of 
progression, will not be sufficient for definition of progressive disease in the first 24 weeks 
after completion of radiation.  Follow-up brain MRI with and without contrast per standard 
of care will be used in the assessment of the evolution of these lesions.  Further increase 
in enhancement in subsequent MRI warranting a change in therapy per the treating 
physician will define progression unless proven otherwise by a histopatholigcally 
confirmed diagnosis.  Lesions that stabilize or reduce in size will be deemed consistent 
with pseudoprogression. 
 
Radiation Exposure (dosimetry). Radiation exposure from 11C-CH PET imaging study has been 
estimated and published.[55, 56] The critical organ exposures are: kidney 0.64, bladder wall 0.36, 
and liver 0.26 cGy/mCi with all other organs  receiving  less than 0.25 cGy per mCi injected. Doses 
to the most radiation sensitive tissues red marrow,  testes and ovaries  are 0.075, 0.057, and 0.067 
cGy/mCi respectively.  The RDRC  requires  that the administered activity result in <30mSv to the 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-676 A(6) 
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Page 13 of 23 
 
 
 
 
 
radiosensitive  tissues that include the lens of the eye, gonads, bone marrow,  and GI tract, and 
<50mSv for all other organs  per administration.  Dosimetry data for lens of the eye was not 
available  (visual  uptake of F-choline was not observed  for this organ).   Additionally, if more than 
one administration of the radiotracer will be given,  then the study must ensure <50mSv for the 
radiosensitive  organs  and <150mSv for all other organs within a single year.  These factors taken 
together influenced the selection of a total administered activity of not more than 14mCi for this 
study in order to be within compliance with the RDRC dosimetry regulations.   The organ dose 
estimates from this study are provided  in Table 3. 
 
Radiosynthesis and Specific Activity of 11C- CH.   The 11C-CH drug product will be manufactured  in 
compliance with the current Good Manufacturing  Practices (cGMP) requirements  at the MSKCC 
Radiochemistry  and Molecular Imaging Probes Core Facility, using the ORA Neptis automated 
synthesizer. The synthesizer cassettes, and reagents  and materials will be supplied by ABX 
Advanced  Biochemical Compounds  (Radeberg,  Germany). 11C-choline  injection contains 30 mCi 
to 400 mCi in approximately  10 ml of 11C-choline  at EOS (End of Synthesis) calibration time in 
aqueous  0.9% sodium chloride solution.  The patient unit dose will consist of 10-20 mCi of 11C- 
choline. With a molecular weight of 104, 20 mCi of 11C-choline  corresponds  to 104 mg/mmol x 
2x10-6 mmol = 200x10-6  mg = 2x10-4 mg of administered.  All manufactured  18F-FCH drug product 
batches will be Quality Control  (QC) tested to ensure conformance  with the acceptance 
specifications for pH, appearance,  radiochemical  purity, radiochemical  identity, radionuclidic  
identity, endotoxin levels,  sterilizing filter integrity, and residual solvent  levels  prior to release for 
patient administration. Sterility testing will performed  post release. 
 
11C-CH Delivery  to the MITS Radiopharmacy  from  Radiochemistry  (RMIP) Core. 11C-CH dose will 
be delivered  by Radiochemistry  (RMIP) Core to MITS  Clinical Radio-pharmacy  in Nuclear   
Medicine. MITS Clinical Nuclear Pharmacist receives  the delivery  from  RMIP Core and ensures   
that the study drug is handled, inventoried,  stored properly, labeled and dispensed as per AU MITS 
Physician prescription order.  The  11C-CH dose will be drawn and measured in a Dose Calibrator by 
a MITs Nuclear Pharmacist prior to dispensing. Then,  the syringe will be placed in a shielded  
Carrier and handed  over to AU MD or designee for administration. After the dose administration the 
AU MD returns the Syringe for Residual Measurement  by MITS  Nuclear Pharmacist. All MITS 
Radiopharmacy  activity will be documented  by MITS  Nuclear Pharmacist. 
 
PET imaging Protocol. Patients will undergo PET scanning following  intravenous  administration of 
up to 10-20 mCi (6-20mCI  to permit for decay) of 11C-CH under the regulation and approval  of the 
MSKCC RDRC.  10-20 mCi of 11C-choline  will be administered intravenously  as a bolus, followed 
by 10-30 mL of normal saline flush, with the patient already placed on the bed of the scanner unit. 
Imaging will begin approximately 5 minutes after injection of 11C-choline.We  will accrue 6 
evaluable  research subjects with the purpose of determining  the biodistribution within the evolving 
lesion. No information  gleaned from the PET images or biodistribution data shall be used to affect 
patient  management. 
 
Patients will be set up for a static single field of view (15 cm) head scan by means of a scout and 
low-dose CT scan. 11C-CH will be administered as an intravenous  slow bolus with simultaneous 
initiation of the scan sequence. The patient will be positioned in the PET/CT in the scan ready 
position prior to the radiopharmacy  dispensing the 11C-CH activity. In this way the activity 
administered to the patient is within 10% of the prescribed activity as required by research PET 
studies. 11C-CH, for intravenous  bolus injection, is a PET imaging agent with a half-life  of 20.4 min. 
Prior studies have shown that tracer uptake plateaus within 15-20 minutes post-injection. A single 
PET scan will be performed  for up to a maximum of 40 min to ensure capture of the uptake. 
 
PET Imaging Analysis.  The procedures  described above  will yield a number of parameters  that 
individually  or in specific combinations  will be assessed in their ability to distinguish treatment 
related changes  from recurrent  tumor. A positive 11C-CH PET study, one which is believed  to 
indicate recurrent  tumor, is one in which there are visible focal “hot spots” (a focus of lesion/normal 
white matter ratio >1.4) of 11C-CH. 

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IRB Number: 16-676 A(6) 
Approval date: 11-Sep-2019 
Page 14 of 23 
 
 
 
 
8.0 
TOXICITIES/SIDE EFFECTS 
 
The recommended daily dietary intake of choline is 500mg per day and the maximum safe level of 
choline is 3.5 g/day. The amount of 11C-CH to be administered will be at tracer micrograms levels, 
which are orders of magnitude below the safety limits for choline. Therefore chemical toxicity is  
not expected. No toxicities associated with “tracer doses” of 11C-CH have been reported. The 
dose-limiting toxicity is therefore associated solely with the radiation emissions emanating from  
the 11C radiolabel. The activities of 11C-CH that shall be administered will be up to 10-20 mCi 
(approximately 6-20mCi). The expected radiation doses from this maximum administration level of 
20 mCi is given in total dose column of the table below, which also includes the 0.9 cGy 
contribution from the low-dose CT (Table 3). Exposure falls within the constraints imposed by an 
RDRC protocol. 
While toxicities are not anticipated on this trial, all patients will have a follow up toxicity 
assessment by a member of the reasearch team (MD, NP, or RN), either in person or over the 
phone, 1-3 days following the research scans. The participants will be asked whether they have 
suffered any adverse events and these will be documented. 
Table 3. Radiation Dosimetry Estimates 
 
11C-Choline and Head CT Dosimetry 
 
 
 
11C-Choline 
Imaging: 
rad / 
Pre-surgical: 
rad / 
Low-dose 
Total 
10.0 
2.0 
Head CT 1 
Dose 
Target  Organ 
rad/mCi 
mCi 
mCi 
rad 
rad 
Adrenals 
0.0630 
0.630 
0.126 
0 
0.819 
Brain 
0.0290 
0.290 
0.0580 
0.9 
1.28 
Breasts 
0.0310 
0.310 
0.0620 
0 
0.403 
Small Intestine 
0.0480 
0.480 
0.096 
0 
0.624 
Large  Intestine 
0.0480 
0.480 
0.096 
0 
0.624 
Stomach Wall 
0.0480 
0.480 
0.096 
0 
0.624 
Kidneys 
0.289 
2.89 
0.578 
0 
3.76 
Liver 
0.207 
2.07 
0.414 
0 
2.69 
Lungs 
0.0410 
0.410 
0.0820 
0 
0.533 
Muscle/Other Tissue 
0.0370 
0.370 
0.0740 
0 
0.481 
Pancreas 
0.0590 
0.590 
0.118 
0 
0.767 
Red Marrow 
0.0370 
0.370 
0.0740 
0.9 
1.38 
Bone surface 
0.0560 
0.560 
0.112 
0.9 
1.63 
Skin 
0.0290 
0.290 
0.0580 
0 
0.377 
Spleen 
0.111 
1.11 
0.22 
0 
1.44 
Gonads 
0.0340 
0.340 
0.0680 
0 
0.442 
Thymus 
0.0370 
0.370 
0.0740 
0 
0.481 
Thyroid 
0.0350 
0.350 
0.0700 
0.9 
1.36 
Urinary  Bladder Wall 
0.107 
1.07 
0.214 
0 
1.39 
 
1 
For bone surfaces, red marrow,  and thyroid, the low-dose  CT absorbed 
doses are conservatively   estimated as if they were completely in the CT 

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IRB Number: 16-676 A(6) 
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Page 15 of 23 
 
 
 
 
 
field of view.   All other organs  were assigned a CT dose of 0, since they 
would receive only a  negligibly  small scatter dose. 
 
 
9.0 
PRIMARY OUTCOMES 
We will assess 11C-CH tracer biodistribution within high-grade glioma lesions with MRI findigns 
concerning for pseudoprogression vs. true tumor progression after treatment with radiation.  PET 
imaging metrics will be collected; peak SUV values in the lesion and the tumor to background 
ratio will be compared to clinical follow-up outcomes based on MRIs. 
We expect that there will be low uptake of 11C-CH in perilesional normal brain tissue and SUV 
measures will correlate with clinical follow-up outcomes, thus supporting more definitive 
investigation of 11C-CH PET to noninvasively distinguish recurrent tumor (true tumor progression) 
from necrosis and inflammation (pseudoprogression) in post-treatment MRI-evolving brain 
lesions. 
 
10.1 CRITERIA FOR REMOVAL FROM STUDY 
 
▪ 
Inability to undergo PET/CT scan. 
▪ 
Found  to  be  ineligible  for  the  protocol  as  described  in  the  section  on  Criteria  for 
Patient/Subject Eligibility. 
▪ 
Patient and/or legal representative requests to withdraw from study for any reason 
 
▪ 
Referring physician requests  to have patient withdrawn from  study for any reason, 
including believing that it would be in the patient’s best interest. 
 
 
11.0 
BIOSTATISTICS 
 
This trial is a pilot study to determine the distribution of 11C-CH using PET imaging in progressive 
high-grade glioma lesions suspected to represent true tumor progression vs pseudo-progression, 
following treatment with a course of radiation.  The purpose of this trial is to correlate SUV 
measures from 11C-CH PET with evolving changes on brain MRI in high-grade glioma after 
radiotherapy. In a small subgroup of patients required surgery, tissue will be analyzed for 
histopathologic correlate. The data gathered will not be considered definitive, but rather will be 
used to as preliminary data in support of a larger, definitive study. 
 
The biodistribution of 11C-CH will be measured using PET as a basis for dosimetry. This will be 
performed with region of interest analysis. The first objective is to determine the organ/tissue 
uptake and tumor localization following intravenous injection of 11C-CH in patients with high-grade 
glioma with radiographic progression concerning for progression versus pseudoprogression 
following treatment with radiation with or without chemotherapy. The group for this analysis 
comprises 6 high-grade glioma patients who appear to have progression vs pseudoprogression 
on standard MRI with contrast. Standardized uptake values (SUV) in the brain will be measured 
and summarized for each patient to describe the organ and tissue uptake of the tracer. The mean 
SUV along with SUVmax value will be estimated in normal and tumor tissue, and lesion-to-normal 
brain ratio (LNR) values will be obtained. All patients will then we followed with surveillance brain 
MRI per standard treatment over a period of 11 months for evolving changes that will confirm the 
diagnosis of progression versus pseudoprogression as defined in the protocol. 

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IRB Number: 16-676 A(6) 
Approval date: 11-Sep-2019 
Page 16 of 23 
 
 
 
 
It is anticipated that 1 patient every 2 months will be accrued to this study and the study will be 
completed in approximately 12 months. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-676 A(6) 
Approval date: 11-Sep-2019 
Page 17 of 23 
 
 
 
 
12.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
12.2 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
During the registration process, registering individuals will be required to complete a 
protocol specific Eligibility Checklist. The individual signing the Eligibility Checklist is 
confirming whether or not the participant is eligibile to enroll in the study. 
Study staff are responsible for ensuring that all institutional requirements necessary to 
enroll a participant to the study have been completed. See related Clinical Research 
Policy and Procedure #401 (Protocol Participant Registration). 
12.3 
Randomization 
No randomization will occur in this study. 
 
13.1 
DATA MANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of 
the RSA include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordinating the activities 
of the protocol study team. 
 
The data collected for this study will be entered into a secure database. Source 
documentation will be available to support the computerized patient record. 
 
 
13.2 
Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and  
completeness of registration data. Routine data quality reports will be generated to assess 
missing data and inconsistencies.  Accrual rates and extent and accuracy of evaluations 
and follow-up will be monitored periodically throughout the study period and potential 
problems will be brought to the attention of the study team for discussion and action. 
 
Random-sample data quality and protocol compliance audits will be conducted by the 
study team, at a minimum of  two times per year, more frequently if indicated. 
 
 
13.3 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address the 
new policies set forth by the NCI in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials,” which can be found at: 
http://www.cancer.gov/clinicaltrials/conducting/dsm -guidelines /page1. 

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IRB Number: 16-676 A(6) 
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Page 18 of 23 
 
 
 
 
The DSM Plans at MSKCC were established and are monitored by the Office of Clinical 
Research. The MSKCC Data and Safety Monitoring Plans can be found on the MSKCC 
Intranet at: 
http://inside2/clinresearch/Documents/MSKCC%20Data%20and%20Safety%20Monitoring 
%20Plans.pdf 
There are several different mechanisms by which clinical trials are monitored for data, 
safety, and quality. There are institutional processes in place for quality assurance (e.g., 
protocol monitoring, compliance and data verification audits, therapeutic response, and 
staff education on clinical research quality assurance) and departmental procedures for 
quality control, plus there are two institutional committees that are responsible for 
monitoring the activities of our clinical trials programs: the Data and Safety Monitoring 
Committee (DSMC) for Phase I and II clinical trials, and the Data and Safety Monitoring 
Board (DSMB) for Phase III  clinical trials, report to the Center’s Research Council and 
IRB. 
During the protocol development and review process, each protocol will be assessed for 
its level of risk and degree of monitoring required.  Every type of protocol (e.g., NIH 
sponsored, in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be 
addressed and the monitoring procedures will be established at the time of protocol 
activation. 
14.1 
PROTECTION OF HUMAN SUBJECTS 
 
Risks: There are no expected additional risks to the patients who participate in this study. 
Patients will receive the current standard of care for their disease. PET/CT is considered a 
minimal risk procedure. FDG PET/CT is a standard diagnostic test utilized in the 
management of patients with high grade gliomas. 18F-FCH PET is not standard but poses 
no risk other than a very minimal radiation exposure as detailed above. No additional risks 
have been reported in patients receiving 18F-FCH PET scans. Patients may experience 
pain and/or discomfort related to the IV catheter, but they would commonly require IV 
contrast for their routine scans in any case. 
Costs: The patient and/or patient’s insurance will be responsible for all charges, which are 
part of the standard of care. No financial reimbursement or other financial incentive will be 
provided for patients to enroll in this study. There will be no charge for the 18F-FCH 
PET/CT studies or the tissue analysis of radioactivity levels. 
Benefits: We do not expect patients to derive any clinical benefit from this clinical trial. We 
hope that in the future, knowledge from this trial will help better evaluate diagnostic 
procedures for these diseases. 
All patients will sign informed consents and have all their questions fully addressed before 
enrolling in this study. During the informed consent process, it will be made clear to the 
potential patient that participation is entirely voluntary, and will not impact the care that 
they receive at MSKCC. Potential patients will be advised of alternatives to the proposed 
study, including not participating in the study. All the data will be held confidential, 
maintained in a password protected electronic database, and comply with all HIPAA 
guidelines. 
 
 
14.2 
Privacy 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-676 A(6) 
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Page 19 of 23 
 
 
 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure 
of protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
The consent indicates that individualized  de identified information collected for the 
purposes of this study may be shared with other qualified researchers. Only researchers 
who have received approval from MSK will be allowed to access this information which will 
not include protected health information, such as the participant’s name, except for dates. 
It is also stated in the Research Authorization that their research data may be shared with 
other qualified researchers. 
 
 
14.3 
Serious Adverse Event (SAE) Reporting 
 
 
 
An adverse event is considered serious if it results in ANY of the following 
outcomes: 
• Death 
• A life-threatening adverse event 
• An adverse event that results in inpatient hospitalization or prolongation of 
existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• A congenital anomaly/birth defect 
• Important Medical Events (IME) that may not result in death, be life threatening, 
or require hospitalization may be considered serious when, based upon 
medical judgment, they may jeopardize the patient or participant and may 
require medical or surgical intervention to prevent one of the outcomes listed in 
this definition 
 
Note: Hospital admission for a planned procedure/disease treatment is not 
considered an SAE. 
 
SAE reporting is required as soon as the participant starts investigational 
treatment/intervention. SAE reporting is required for 30-days after the participant’s 
last investigational treatment/intervention. Any event that occur after the 30-day 
period that is unexpected and at least possibly related to protocol treatment must 
be reported. 
 
Please note: Any SAE that occurs prior to the start of investigational treatment/intervention 
and is related to a screening test or procedure (i.e., a screening biopsy) must be reported. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-676 A(6) 
Approval date: 11-Sep-2019 
Page 20 of 23 
 
 
 
 
 
 
All SAEs must be submitted in PIMS. If an SAE requires submission to the HRPP 
office per IRB SOP RR-408 ‘Reporting of Serious Adverse Events’, the SAE report 
must be submitted within 5 calendar days of the event.  All other SAEs must be 
submitted within 30 calendar days of the event. 
The report should contain the following information: 
 
• The date the adverse event occurred 
• The adverse event 
• The grade of the event 
• Relationship of the adverse event to the treatment(s) 
• If the AE was expected 
• Detailed text that includes the following 
o An explanation of how the AE was handled 
o A description of the participant’s condition 
o Indication if the participant remains on the study 
• If an amendment will need to be made to the protocol and/or consent form 
• If the SAE is an Unanticipated Problem 
 
 
14.2.1 
 
This is not an Industry or Cooperative group protocol.  This protocol does not have an 
IND. 
15.1 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain 
full details of the protocol and study procedures as well as the risks involved to  
participants prior to their inclusion in the study. Participants will also be informed that they 
are free to withdraw from the study at any time. All participants must sign an IRB/PB- 
approved consent form indicating their consent to participate. This consent form meets the 
requirements of the Code of Federal Regulations and the Institutional Review 
Board/Privacy Board of this Center. The consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of 
supportive care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and 
to withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional 
will fully explain the aspects of patient privacy concerning research specific information.  In 

Memorial Sloan Kettering Cancer Center 
IRB Number: 16-676 A(6) 
Approval date: 11-Sep-2019 
Page 21 of 23 
 
 
 
 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant 
must receive a copy of the signed informed consent form. 
16.0 
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Brandes AA, Franceschi E, Tosoni A et al. MGMT  promoter methylation status can predict 
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Sanghera P, Perry J, Sahgal A et al. Pseudoprogression following chemoradiotherapy for 
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Approval date: 11-Sep-2019 
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