Clinical trial NCT00597246
Conditions: Brain Cancer CNS Cancer
Keywords: Brain CNS Central Nervous System
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2003-05-13; Completion date: 2019-11-27
Enrollment: 30 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This research protocol makes pictures of brain tumors. The pictures are made with a positron emission tomography (PET) scanner. PET scans use radioactivity to "see" cancer cells. We are using a new kind of PET scan. The new PET scan is called \[18F\]-FACBC PET. We will compare this to the standard PET scan. The standard PET scan is called \[11C\]-methionine PET.

We expect these pictures will give us information about your tumor. We also hope to collect information about the amount of radioactivity exposure. We will measure radioactivity exposure to your tumor, brain and other organs. The research study results will be used to support the submission of an investigational new drug (IND) application to the Food and Drug Administration (FDA).

Detailed description:
The purpose of this research is to: 1) perform both 3-\[18F\]-FACBC and \[11C-methyl\]-Lmethionine brain tumor PET imaging studies in patients with primary brain tumors who have previously been treated and are now suspect for having recurrence or progression of disease (a pilot study, n=20); 2) perform only 3-\[18F\]-FACBC PET imaging studies on an additional set of patients with primary brain tumors who have previously been treated and are now suspect for having recurrence (n=10) . 3) obtain organ/tissue and body radiation dosimetry information following i.v. injection of 3-\[18F\]-FACBC; 4) look for potential correlations between the scan results obtained from those patients enrolled to 03-028 and the patients' past medical treatment; The first set of 20 patients will agree to two PET studies. One study will involve the i.v.

administration of a fluorine-18 labeled amino acid analogue, 3-fluoro-aminocyclobutane carboxylic acid (3-\[18F\]-FACBC) with sequential brain and body PET imaging. The second study will involve i.v. administration of \[11C-methyl\]-L-methionine and head imaging only.

The additional set of 10 patients will undergo one PET study which will consist of the i.v.

administration of fluorine-18 labeled amino acid analogue, 3-fluoro-aminocyclobutane carboxylic acid (3-\[18F\]-FACBC) with one brain scan and one body scan only. The 3-\[18F\]-FACBC PET studies (n=30) will be performed under the Radioactive Drug Research Committee (RDRC) guidelines as defined and established by the Federal Drug Administration (FDA). \[11C-methyl\]-L-methionine is in the hospital formulary and is approved for imaging brain tumors at MSKCC. Our hypotheses include: 1) \[18F\]-FACBC has equal or better brain tumor imaging characteristics compared to \[11C\]-methionine; 2) \[18F\]-FACBC is not metabolized, and radiolabeled metabolites will not confound the interpretation of the images as can be the case with \[11C\]-methionine; 3) imaging recurrent brain tumors with \[18F\]-FACBC will be enhanced by lower brain (background) activity as compared to corresponding \[11C\]- methionine images; 4) the biodistribution of \[18F\]-FACBC and radiation dosimetry following i.v. administration of a 370 MBq (10 mCi) dose is safe and within FDA guidelines; 5) a 370 MBq (10 mCi) dose of \[18F\]-FACBC is sufficient for imaging brain tumors in a clinical setting; 6) the accumulation of \[18F\]-FACBC will correlate with the patients response to prior treatment and will provide prognostic information with respect to tumor progression and survival.

Arms: arm 1: None
Interventions: intervention 1: FACBC, Methionine intervention 2: PET Scan
Intervention descriptions: intervention 1: F-18 labeled FACBC is prepared stereo-specifically in a semi-automated, NCA procedure utilizing the General Electric FDG MicroLab, a system employing a quaternary 4-aminopyridinium resin to effect F-18 fluorination. The triflate species is displaced with F-18 fluoride in the MicroLab, and then the 1-t-butyl carbamate-3- trifluoromethane sulfonoxy-1-cyclobutane-1-carboxylic acid methyl ester is hydrolyzed with 1 N HCl. The final product is isotonic and sterile, and has been utilized in animal experiments. The product was obtained in 30% radiochemical yield after 65 minutes from EOB. The radiochemical purity was greater than 95% and no preparative HPLC was required. The procedure could be considered routine, and is performed on the FDG synthetic module without changes either to the programming or to the cassettes. intervention 2: GE Advance PET scanner for sequential body imaging

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 03-028 A(11) 
Page 1 of 16 
 
 
 
 
 
 
 
 
 
onine 
 
L 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Ave. 
New York, N.Y. 10021 
Approval date: 22-Sep-2017 
Imaging Brain Tumors with FACBC and Methi
THERAPEUTIC/DIAGNOSTIC PROTOCO 
Principal Investigator: 
Ronald Blasberg, M.D. 
Neurology: Neurology 
Co-Principal Investigator(s): Steven M. Larson, M.D. 
Radiology: Nuclear Medicine 
Wolfgang Weber, M.D. 
Radiology: Nuclear Medicine 
Laure Michad, B.A. 
Radiology: Nuclear Medicine 
Investigator(s): 
Bradley Beattie, M.S. 
Neurology: Neurology 
John L. Humm, Ph.D. 
Medical Physics: Clinical Physics 
Ira Dunkel, M.D. 
Pediatrics: Pediatrics 
Lisa DeAngelis, M.D 
Neurology: Neurology 
Craig Nolan, M.D 
Neurology: Neurology 
Igor Gavrilovic, M.D. 
Neurology: Neurology 
Consenting Professional(s): 
Ronald Blasberg, M.D. 
Steven M. Larson, M.D. 
Igor Gavrilovic, M.D. 
Lisa DeAngelis, M.D 
Craig Nolan, M.D 
Wolfgang Weber, M.D. 
Laure Michad, B.A. 


Page 2 of 16 
Memorial Sloan Kettering Cancer Center 
IRB Number: 03-028 A(11) 
Approval date: 22-Sep-2017 
 
 
 
 
SUMMARY AND/OR SCHEMA 
 
The purpose of this research is to: 1) perform both 3-[18F]-FACBC and [11C-methyl]- L- 
methionine brain tumor PET imaging studies in patients with primary brain tumors who have 
previously been treated and are now suspect for having recurrence or progression of disease 
(a pilot study, n=20); 2) perform only 3-[18F]-FACBC PET imaging studies on an 
additional set of patients with primary brain tumors who have previously been treated and are 
now suspect for having recurrence (n=10) .   3) obtain organ/tissue and body radiation 
dosimetry information following i.v. injection of 3-[18F]-FACBC; 4) look for potential 
correlations between the scan results obtained from those patients enrolled to 03-028 and the 
patients’ past medical treatment; 
 
The first set of 20 patients will agree to two PET studies. One study will involve the i.v. 
administration of a fluorine-18 labeled amino acid analogue, 3-fluoro-aminocyclobutane 
carboxylic acid (3-[18F]-FACBC) with sequential brain and body PET imaging. The second 
study will involve i.v. administration of [11C-methyl]-L- methionine and head imaging only. 
 
The additional set of 10 patients will undergo one PET study which will consist of the i.v. 
administration of fluorine-18 labeled amino acid analogue, 3-fluoro-aminocyclobutane 
carboxylic acid (3-[18F]-FACBC) with one brain scan and one body scan only. 
 
The 3-[18F]-FACBC PET studies (n=30) will be performed under the Radioactive Drug 
Research Committee (RDRC) guidelines as defined and established by the Federal Drug 
Administration (FDA). [11C- methyl]-L- methionine is in the hospital formulary and is 
approved for imaging brain tumors at MSKCC. 
 
Our hypotheses include: 1) [18F]-FACBC has equal or better brain tumor imaging 
characteristics compared to [11C]- methionine; 2) [18F]-FACBC is not metabolized, and 
radiolabeled metabolites will not confound the interpretation of the images as can be the case 
with [11C]- methionine; 3) imaging recurrent brain tumors with [18F]-FACBC will be 
enhanced by lower brain (background) activity as compared to corresponding [11C]- 
methionine images; 4) the biodistribution of [18F]-FACBC and radiation dosimetry 
following i.v. administration of a 370 MBq (10 mCi) dose is safe and within FDA guidelines; 
5) a 370 MBq (10 mCi) dose of [18F]-FACBC is sufficient for imaging brain tumors in a 
clinical setting; 6) the accumulation of [18F]-FACBC will correlate with the patients 
response to prior treatment and will provide prognostic information with respect to tumor 
progression and survival. 
 
The results of this study will be used to support the submission of an investigational new 
drug (IND) application to the Food and Drug Agency (FDA). 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
2.1 
Demonstrate in a pilot study (n=30) that [18F]-FACBC has equal or better brain 
tumor imaging characteristics compared to [11C]-methionine. 


Page 3 of 16 
Memorial Sloan Kettering Cancer Center 
IRB Number: 03-028 A(11) 
Approval date: 22-Sep-2017 
 
 
 
 
2.2 
Determine the biodistribution and clearance of 3-[18F]-FACBC in different 
tissues/organs of the body using PET, and calculate body and critical organ 
radioactivity exposure (dosimetry). 
 
2.3 
The results of this study will be used to support the submission of an 
investigational new drug (IND) application to the Food and Drug Agency (FDA). 
 
2.4 
Look for potential correlations between subsequent MR and PET scan results 
obtained from those patients enrolled to 03-028 and the patients’ subsequent 
medical treatment, progression of the tumor and survival. 
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1 
A frequent question that neurooncologists and neurosurgeons must address in the 
management of post-treatment primary brain tumors, is whether a new or expanding 
brain lesion observed on CT or MR imaging represents recurrent tumor, treatment 
effects or tissue necrosis [1-6]. This is of particular concern in the management of 
patients with previously treated low- grade or anaplastic gliomas. Frequently, a patient 
may have little or no change in clinical neurological status on follow-up clinical visits, 
but changes in the pattern of contrast enhancement or an expansion of T2, FLAIR or 
diffusion abnormalities are observed on routine MRI. The question of recurrent disease 
vs. treatment effect is frequently raised by clinicians in this setting. This question often 
leads to further studies or a surgical procedure (e.g., needle or open biopsy) to resolve 
this issue or to confirm the diagnosis of recurrent tumor. The number of needle biopsy 
specimens is usually limited in surgical practice (due to the risk of hemorrhage) and it 
is not uncommon for the pathology of the biopsy sample(s) to be read as nonspecific 
“gliosis” or “inconclusive”. 
 
3.2 
The "functional" imaging capabilities of PET can provide important additional 
information that will facilitate making patient management decisions. [18F]- fluoro-2- 
deoxyglucose ([18F]FDG) PET imaging has been used to distinguish recurrent tumor 
from treatment effects and tissue necrosis for almost two decades.  More recently, the 
advantages of [methyl-11C]- methionine ([11C]MET) PET imaging of brain tumors 
have been documented in Europe and Japan [7-10].   Functional information, such as 
glucose utilization and amino acid transport, can be obtained from PET imaging, and 
these functional/metabolic/transport images are now routinely compared to the 
abnormal CT or MR images.  This comparison is particularly robust fo llowing digital 
registration of the PET and MR/CT images (see below), and provides very useful 
information for making timely patient management and treatment decisions. 
 
3.3 
The current medical management of brain tumor patients with inconclusive changes on 
MRI usually involves repeating the MRI in three months. Serial MRI comparisons are 
performed to determine whether there is significant progression in the abnormalities. 
Monitoring changes in serial MRI’s is considered to be the standard of care for the 
neurological and neurosurgical management of patients with primary brain tumors. 
However, such changes can be subtle and occur over an extended period of time, 
particularly for low or intermediate (anaplastic) grade gliomas. The several month 


Page 4 of 16 
Memorial Sloan Kettering Cancer Center 
IRB Number: 03-028 A(11) 
Approval date: 22-Sep-2017 
 
 
 
 
interval required to document a significant change on MRI can delay initiating a new 
treatment or the surgical resection of a recurrent tumor. The assessment of recurrent 
disease is a frequent quandary in the management of patients with primary brain 
tumors. 
 
3.4 
Alternatively, a patient may undergo a biopsy or surgical procedure to address the 
question of recurrent disease. We suggest that many surgical procedures could be 
avoided based on a negative functional PET scan, or the surgical resection or biopsy 
could be targeted to the site that is identified in the functional PET scan most likely to 
represent recurrent tumor. As a consequence, the management of patients with 
suspected recurrent gliomas frequently involves multimodality imaging assessments at 
MSKCC.  We have found that multimodality imaging assessments result in more rapid 
patient management decisions for initiating new treatments as well as sparing some 
patients a surgical procedure (e.g., needle biopsy or craniotomy. 
 
3.5 
[18F]-FACBC PET studies in human subjects have been performed at Emory [11]; the 
images from this study are shown in Figure 1. 
 
 
 
Figure 1 
 
Although [18F]-FACBC PET studies in patients have yet to be performed at MSKCC, 
[11C]- methionine and [18F]-FDG are in clinical use for evaluating patients with 
suspected recurrent brain tumors, as well as patients who are noted to have a new but 
inconclusive changes in their MR scans. PET imaging with these two tracers (along 
with Gd-DTPA T1, T2 and FLAIR MR images for the brain) are currently being used to 
further assess these patients and address clinical management issues. The proposed 
[18F]-FACBC PET imaging studies will be integrated into this established framework 
for clinical brain tumor assessment. 


Page 5 of 16 
Memorial Sloan Kettering Cancer Center 
IRB Number: 03-028 A(11) 
Approval date: 22-Sep-2017 
 
 
 
 
3.6 
Significant points and rationale for imaging brain tumors with FACBC. FDG and 
methionine imaging of brain tumors have some significant limitations that are likely to 
be addressed by imaging with FACBC.  First, the interpretation of FDG images of  
solid tumors is often confounded by the multiplicity of factors that increase glycolysis 
(factors other than cell proliferation), such as tissue hypoxia and the infiltration of 
inflammatory cells.  Second, FDG images of brain tumors are often difficult to interpret 
because of the relatively "high" metabolic activity of surrounding brain tissue;  this 
results in relatively "low" tumor-to-brain activity ratios (contrast), particularly when 
compared to the activity ratios (contrast) observed in FDG body images of systemic 
tumors and metastases (e.g., lung, colon, etc.). Third, the relatively "low" tumor-brain 
contrast in the FDG images frequently requires PET-MR image registration to more 
clearly identify the tumor margins; FDG-MR image registration has become a standard 
procedure in the clinical evaluation of FDG PET scans of brain tumor patients at 
MSKCC and other institutions. Fourth, FDG images, in contrast to methionine images, 
are not useful for identifying tumor infiltration of adjacent brain tissue (beyond the 
margin of contrast enhancement).  Fifth, the interpretation of methionine images (and 
images of other naturally occurring amino acids) are confounded by the presence of 
radiolabeled metabolites that contribute to the image; ACBC, ACPC and AIB are not 
metabolized in mammals and are excreted unchanged in the urine. Sixth, amino acid 
imaging of tumors benefits from the up-regulation of "A" transporter expression in the 
cell membranes of transformed and malignant tumor cells. Seventh, the amino acid 
transport carriers (both "L" and "A" transport systems) and transport carrier kinetic 
parameters (Bmax) across cell membranes in vitro and endothelial cells (BBB) in vivo 
favor FACBC over methionine (see Tables 1 and 2, and related discussion). Eighth and 
most important for routine clinical applications, tumor imaging with [18F]-FACBC 
would have substantial logistical and cost-effective benefits in a busy nuclear medicine 
department in comparison to imaging with [11C]- methionine 
 
 
4.0 
STUDY DESIGN 
 
4.1 
The first set of 20 patients will consent to two PET stud ies. One study will involve the 
i.v. administration of a fluorine-18 labeled amino acid analogue, 3- fluoro- 
aminocyclobutane carboxylic acid (3-[18F]-FACBC) with sequential brain and body 
PET imaging. The second study will involve i.v. administration of [11C- methyl]-L- 
methionine for a head imaging study only. An additional set of 10 patients will consent 
to one type of PET study which will involve administration of [18F]-FACBC only for 
one brain scan and one body scan. 
 
4.2 
All The first set of 20 patients will first undergo a [11C- methyl]-L- methionine PET 
study. Whenever possible, approximately two hours later, the same patient will undergo 
the [18F]-FACBC PET study. 
 
4.3 
For the first 20 patients, we will attempt to complete both studies on the same day; if 
this is not possible, the two PET studies will be completed within 1 week of each other. 


Page 6 of 16 
Memorial Sloan Kettering Cancer Center 
IRB Number: 03-028 A(11) 
Approval date: 22-Sep-2017 
 
 
 
 
4.4 
The 3-[18F]-FACBC and [11C- methyl]-L- methionine PET images will be digitally 
registered to each other and to corresponding contrast enhanced and FLAIR MR images 
(from the most recent MR study obtained as part of the patient’s standard medical care). 
Region of interest (ROI) measurements of 3-[18F]-FACBC and [11C- methyl]-L- 
methionine activity in tumor and remote brain tissue will be obtained from the two data 
sets and paired comparisons will be performed. 
 
4.5 
The study will also provide data to determine body and critical organ radioactivity 
exposure (dosimetry) following 3-[18F]-FACBC administration. These calculations 
will be based on the biodistribution and clearance of radioactivity from the tissues and 
organs of the body as determined by sequential PET imaging. 
 
4.6 
Look for potential correlations between the MR and PET scan results obtained from 
those patients enrolled to 03-028 and the patients’ past medical treatment, as well as the 
patients’ subsequent medical treatment, progression of the tumor and survival. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1 
Routine production of fluorine-18 labeled FACBC and [11C]- labeled methionine will 
be produced by the Cyclotron-Radiochemistry Core at MSKCC for human 
administration [Appendix A]. 
 
F-18 labeled FACBC is prepared stereo-specifically in a semi-automated, NCA 
procedure utilizing the General Electric FDG MicroLab, a system employing a 
quaternary 4-aminopyridinium resin to effect F-18 fluorination. The triflate species is 
displaced with F-18 fluoride in the MicroLab, and then the 1-t-butyl carbamate-3- 
trifluoromethane sulfonoxy-1-cyclobutane-1-carboxylic acid methyl ester is hydrolyzed 
with 1 N HCl. The final product is isotonic and sterile, and has been utilized in animal 
experiments.  The product was obtained in 30% radiochemical yield after 65 minutes 
from EOB.  The radiochemical purity was greater than 95% and no preparative HPLC 
was required.  The procedure could be considered routine, and is performed on the FDG 
synthetic module without changes either to the programming or to the cassettes. 
 
Because of the deliberately closed design of the MicroLab, the only variables readily 
changeable include the contents and concentrations of the four reagent vials feeding 
into the system, and the makeup of the final purification columns attached to the 
cassettes.  The MicroLab features a single-use, disposable cassette (see Appendix 2) in 
which the starting syntheton is slowly passed through a small heated column of a 
quaternary 4-aminopyridinium resin on which has been absorbed the F-18 anion. As 
the fluorination occurs on the resin, it is carried in an organic solvent to the hydrolysis 
vessel, where in subsequent steps, the hydrolytic deprotection occurs.  Finally, the pH is 
adjusted with buffer, and the whole mixture is filtered, in succession, through various 
filtration cartridges. The fluorine-18 labeled trans-FACBC passed testing for toxicity, 
radiochemical purity, radionuclidic purity, sterility and apyrogenicity. 
 
5.2 
L-[methyl- 11C]-methionine is prepared in the Cyclotron Facility at MSKCC according 
to the method reported by Comar [12]. Approximately 60% radiochemical yield (decay 


Page 7 of 16 
Memorial Sloan Kettering Cancer Center 
IRB Number: 03-028 A(11) 
Approval date: 22-Sep-2017 
 
 
 
 
corrected to methyl iodide reaction) has been obtained with radiochemical purity 
approaching 100% as determined by HPLC and radio TLC.  No chemical impurity 
associated with the starting L-homocysteine thiolactone could be detected. The 
measured specific activity of the product was 250-350 mCi/umole decay corrected to 
start of synthesis. Routine synthesis time is approximately 45 minutes.  The finished 
radiopharmaceutical has successfully passed testing for general safety, sterility and 
apyrogenicity. 
 
6.1 
CRITERIA FOR PATIENT/SUBJECT ELIGIBILITY 
 
The criteria for patient selection will include patients registered at Memorial Hospital 
with a diagnosis of a primary brain tumor and are suspect for having recurrent disease. 
Patients will be nonpregnant, have a Karnofsky score of 60 or more, and have no known 
medical contraindications to MRI and PET scans. The total number of patients expected 
to enter the protocol is 30. There will be no exclusions based on age, sex or ethnic 
background; a pregnancy test will be required of women of child-bearing age.  Pregnant 
women will be excluded from this study. 
 
6.2 
PATIENT/SUBJECT INCLUSION CRITERIA 
 
• 
Registered patient at MSKCC. 
 
• 
Child-bearing age females must be non-pregnant, non-lactating, and must 
be using adequate contraception or surgically sterile. 
 
• 
Karnofsky score of 60 or greater. 
 
• 
Children that can sit still for 60-90 minutes, without sedation, will be 
included in this protocol. 
 
6.3 
PATIENT/SUBJECT EXCLUSION CRITERIA 
 
• 
Patient cannot tolerate lying still for 90 minute sessions in the PET 
tomograph. 
 
7.0 
RECRUITMENT PLAN 
 
7.1 
Recruitment of patients will be through the participating investigators and referrals 
from staff physicians at Memorial Hospital.  A detailed description of the study 
procedures will be provided to each referring physicia n and a simpler version to each 
patient by the principal investigator or one of the senior investigators of this research 
proposal. 
 
7.2 
The signed IRB consent form will be brought to the patient protocol accrual (PPA) 
system in the Data Management Resource Group of the Dept. of Biostatistics and 
Epidemiology at MSKCC for registration at MSKCC, and the imaging study requisition 
for the imaging protocol will be brought to the Department of Nuclear Medicine. 


Page 8 of 16 
Memorial Sloan Kettering Cancer Center 
IRB Number: 03-028 A(11) 
Approval date: 22-Sep-2017 
 
 
 
 
8.0 
PRETREATMENT EVALUATION 
 
Primary pre-treatment evaluation will be based on the evaluation performed as part of the 
patient’s regular medical care at MSKCC. No additional pre-treatment evaluation will be 
performed. 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
9.1 
All subjects will be pre-registered at MSKCC and will have signed the consent form 
prior to participation in this study. 
 
9.2 
The morning of the PET imaging studies, all patients will be asked to avoid high protein 
foods (meat, fish, poultry, cheese, eggs, beans and nuts) and to record the types         
and servings of the foods they eat.  Some patients may also be asked to avoid high 
protein foods the day prior to imaging.  These same patients will also be asked to  
refrain from eating lunch on the day of the study to reduce muscle uptake of the 
FACBC. All patients will also be urged to drink several glasses of water to attain good 
hydration and urine output. Patients will be placed comfortably on the couch and 
positioned in the GE Advance PET scanner. The first 20 patients will first receive 185 
MBq (5 mCi) of: [11C-methyl]- L-methionine by i.v. infusion over approximately 1 
minute. Whenever possible, approximately 1.5 to 2 hours later, the same patient will 
receive 370 MBq (10 mCi) [18F]-FACBC by i.v. infusion over approximately 1 minute. 
In cases where both studies cannot be obtained on the same day, they will be obtained 
within one week of each other. 
 
9.3 
For the first 20 patie nts, the [11C-methyl]- L-methionine study will involve a 45-minute 
emission dynamic scan of the head. Previous studies have shown that [11C-methyl]-L- 
methionine accumulation in tumor and brain tends to reach a plateau value within 15-30 
minutes following administration. The [18F]-FACBC study will involve a 45- minute 
emission dynamic scan of the head to obtain kinetic information on tumor uptake for 
modeling. After the initial dynamic scan, the patient will void completely; the volume of 
urine will be recorded and a urine sample will be assayed for urine radioactivity. Up     
to three [18F]-FACBC body scans will be performed following the completion of the 
dynamic scan to obtain data for calculating body and organ specific dosimetry.  The last 
10 patie nts will undergo a [18F ]-FACBC 45-minute e missio n d yna mic sca n o f the he ad   
fo llo wed b y o ne bod y sca n.   
 
9.4 
A venous catheter will be placed in a superficial hand or arm vein for administration of 
the radiopharmaceuticals. A second venous catheter will be placed in the opposite hand 
or arm for “warmed arterialized” venous blood sampling. For the first 20 patie nts, a 
blood sample will be obtained just prior to the injection of [11C- methyl]-L- methionine 
and [18F]-FACBC to measure plasma amino acid concentration at the time of each 
study. Sequential blood samples will be obtained following [18F]-FACBC infusion and 
assayed for whole blood and plasma radioactivity, to check for radiolabeled metabolites 
by HPLC, and to measure plasma amino acid concentration at the time of the study. All 
catheters will be removed at the end of the day. 


Page 9 of 16 
Memorial Sloan Kettering Cancer Center 
IRB Number: 03-028 A(11) 
Approval date: 22-Sep-2017 
 
 
 
 
9.5 
After the [18F]-FACBC head scan and ~10-15 min break period, patients will be placed 
comfortably on the couch and positioned in the GE Advance PET scanner for sequential 
body imaging.  The total time in the scanner for each imaging sequence will be up to 45 
minutes.  For the first 20 pa tie nts, this sequence of scans will be repeated a maximum of 
three times over a four hour post injection period (approximately two 18-F half      
lives). The first body scan sequence will commence ~60 min after [18F]-FACBC 
injection. The second and third sequences will commence at ~2 and ~3 hours post- 
injection of [18F]-FACBC, respectively, with a break between scans. During the 
intervals between scans, the patient will come out of the scanner, exercise and will be 
asked to void completely. To assist correct re-alignment in the scanner for repeat scans, 
the patient’s skin will be “marked” to identify the plane defined by the PET laser during 
the first scan set. On the second and third scans, the technologist will position each 
patient field of view so as to align the laser with the skin markings. 
 
9.6 
Venous blood will be sampled before the methionine and FACBC scans to measure 
plasma amino acid concentrations. Blood samples (1/2 teaspoon per sample) will be 
drawn during the FACBC scans to measure the radioactivity level in your blood. To tal 
blood sampled for the two PET studies will be less than 6 tablespoons (less than 90 ml). 
Whole blood and plasma will be assayed for radioactivity and for radiolabeled 
metabolites by HPLC. 
 
9.7 
The volume of urine voided between scans will be recorded and a urine sample will be 
assayed for urine radioactivity and radiolabeled metabolites by HPLC. This frequent 
urination will reduce bladder exposure and provide a brief “relaxation” period between 
sequential sets of scans, and will facilitate individual patient acceptance and 
compliance during the study. 
 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
 
10.1 
Reconstructed images will be obtained from the PET data; corrections will be made for 
randoms, scatter, dead-time, detector inhomogeneity and attenuation. Image data will 
be calibrated to nCi/cc and decay corrected to the time of injection. Comparisons will 
be made with the most recent MRI study obtained as part of the patient’s standard 
radiographic assessment. The PET and MRI scans will be digitally co-registered using 
established methods at MSKCC to facilitate this comparison. 
 
10.2 
The registered image sets will be displayed simultaneously, facilitating the 
identification of the correspondence between the lesion(s) in each modality. Volumes of 
interest created on one modality will be applied to the other modalities, thus enabling 
direct quantitative comparisons. 
 
10.3 
Two levels of image analysis will be performed. One level will involve two Nuclear 
Medicine physicians (or one Nuclear Medicine physician and one Neurologist) who 
will independently view the full set of registered images. The analysis will involve 
assessment for the presence or absence of disease using a five point visual scoring 
system. These assessments will be blinded to the clinical and pathologic results 
pertaining to the patient, although all imaging studies (including MRI) will be available 


Page 10 of 16 
Memorial Sloan Kettering Cancer Center 
IRB Number: 03-028 A(11) 
Approval date: 22-Sep-2017 
 
 
 
 
(which is standard clinical practice). We chose a five point scale rating disease from 0-4 
in terms of probability for the presence of disease (0=no evidence of tumor, 1=probably 
no evidence of tumor, 2=equivocal for the presence of tumor, 3=probably tumor present, 
4=definitely tumor present). 
 
10.4 
The second level of analysis will be quantitative. Volumes of interest (VOI) will be 
drawn on the lesions that are positive on the 3-[18F]-FACBC scan; VOI’s on remote 
normal white and gray- matter regions of the brain will also be drawn.  The mean of the 
voxel values within each VOI will be determined for each of the dynamic frames of the 
3-[18F]-FACBC study.  Profiles will be generated in units of: 1) standard uptake value 
[SUV = (% dose/g) * body weight] versus time, and  2) the brain tumor-to-gray or 
white matter ratio versus time.  These curves will be evaluated to determine a single, 
near “optimal” tumor imaging time, for each of the patients. The criteria used in 
making this assessment will be target to background contrast, robustness (i.e. time 
insensitivity) and image noise level.  The SUV and ratio values at this “optimal” time 
point will then be compared to similar SUV and lesion to background values 
determined for the corresponding location within the [11C]-methionine scan.. 
 
10.5 
Radiolabeled metabolites of 3-[18F]-FACBC, if any, in plasma and urine will be 
assayed by HPLC and % parent compound vs. time profiles will be constructed for 
plasma and urine, and compared to the tissue radioactivity concentration vs. time 
profiles calculated above and used for calculating the kinetic parameters. 
 
10.6 
The absorbed tissue radioactivity dose estimates for 3-[18F]-FACBC will be calculated 
in the standard manner. Attenuation corrected PET images provide information for the 
tumor and organ activities directly in units of activity per cubic centimeter. Regions of 
interest will be drawn within identified normal organs e.g. brain, lung, liver, bladder 
etc. This data will be plotted versus time post injection and used for determining organ 
residence times. These organ residence times will be entered into MIRDOSE for 
determination of the organ dosimetry. MIRDOSE is a personal computer software 
package for internal dose assessment from tracers used in nuclear medicine [13]. This 
program calculates the radiation dose to each organ from the activity residing within 
that organ, as well as the contribution of the penetrating photon emissions from other 
body organs accumulating significant levels of radioactivity, according to the 
methodology laid out by the Medical Internal Radiation Dose (MIRD) Committee [14] 
(MIRD PRIMER 1988). 
 
The plasma and urine radioactivity concentration data (nCi/cc) will be plotted vs. time 
after injection. The integral of activity-time curve will be calculated from zero to 
infinity and multiplied by the equilibrium dose constant for 18F to obtain the absorbed 
dose to blood. The dose to the bladder wall will be determined using the dynamic 
bladder model of Cloutier et al. [15], as implemented in MIRDOSE using measured 
clearance data from urine samples. 
 
The dose estimates described above incorporate estimates of the biological clearance of 
the tracer. Companion calculations will also be performed using the assumption of no 
biological clearance, i.e. only physical decay from the organ maximum. This is a 


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IRB Number: 03-028 A(11) 
Approval date: 22-Sep-2017 
 
 
 
 
conservative “worst case” scenario and does not depend on the accuracy of the organ 
clearance fits. 
 
10.7 
Look for potential correlations between the MR and PET scan results obtained from 
those patients enrolled to 03-028 and the patients’ past medical treatment, as well as the 
patients’ subsequent medical treatment, progression of the tumor and survival. 
 
11.0 
TOXICITIES/SIDE EFFECTS 
 
11.1 
PET Scanning. Potential risks to the patient are small, and present more of an 
inconvenience (multiple scans on consecutive days). The GE Advance tomograp h has a 
large bore (92.7 cm in diameter) to accommodate the whole body and the environment 
is much less confining than the head cage of the General Electric Signa 1.5 Tesla MR 
tomograph.  For the first 20 patients, the length of time in the PET scanner will be ~45 
min for the [11C-methionine head scan; for the [18F]-FACBC scan, an initial scanning 
period of the head will be ~45 min, followed by ~45 min for each of the up to three 
subsequent body scan periods (maximum total time in the scanner for the [18F]- 
FACBC imaging series will be ~180 minutes).  The last 10 patients will be scanned for 
a maximum of ~90 minutes (an initial [18F]-FACBC scanning period of the head will 
be ~45 min, followed by a ~45 min body scan).  This is long and could produce some 
discomfort because movement and changes of position will be discouraged. However, 
there will be substantial breaks between each of the [18F]-FACBC imaging sequences 
where the patient will come out of the scanner. Many studies on patients have been 
performed for this length of time and longer. 
 
11.2 
Radiation Exposure.   The radiation exposure from diagnostic 3-[18F]-FACBC or [11C- 
methyl]-L- methionine PET studies is expected to be within acceptable limits as 
established by FDA Guidelines (Code of Federal Regulations, Section 361.1). 
Dosimetry estimates of [11C- methyl]-L- methionine to critical organs have been 
reported [16 and Appendix B]. Preliminary measurements of 3-[18F]-FACBC 
dosimetry performed Emory have been reported [11 and Appendix B] and will be 
extended by results obtained in this study. 
 
11.3 
The dosimetry estimates in Appendices B have led us to select a conservative 185 MBq 
(5 mCi) dose of [11C-methyl]- L-methionine and a 370 MBq (10 mCi) dose of 3-[18F]- 
FACBC for this study. This will maintain the radioactivity exposure to all normal tissue 
(including whole body, blood forming organs and gonads) well below the annual 
radiation dose limit of 5 cSv established by the FDA (Code of Federal Regulations, 
Section 361.1) (see Appendix B).  In the event that our measurements and dosimetry 
estimates for 3-[18F]-FACBC exceed the annual radiation dose limit of 5 cSv 
established by the FDA, we will reduce the administered dose of 3-[18F]-FACBC to 
insure that the annual radiation dose limit of 5 cSv is not exceeded. 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUT COME ASSESSMENT 
 
 
Evaluation of therapy is not the focus of this proposal. 


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Approval date: 22-Sep-2017 
 
 
 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
13.1 
If the patient is no longer able to participate in the protocol and imaging schedule. 
 
13.2 
If the patient’s primary physician and the PI consider that further participation in the 
protocol would not be in the best interest of the patient. 
 
13.3 
If at any time the patient is found to be ineligible for the protocol as designated in the 
section on Criteria for Patient/Subject Eligibility (e.g., a change in diagnosis), the 
patient will be removed from the study. 
 
14.0 
BIOSTATISTICS 
 
14.1 
This is a pilot study involving only 20 30 patients initially.  Basic measurements 
(biodistribution, clearance, radioactivity exposure) will be summarized as means, 
ranges and standard deviations. 
 
14.2 
Published data in humans and our own prior laboratory experience indicate that 
statistical analyses of measurements of the type we propose to study would benefit from 
first applying a logarithmic transformation.  For example, cumulated activities per unit 
of administered activity in Table 3 of [17] had nearly constant coefficients of variation 
(CoV) within subgroups of organs: 24.7% average CoV for brain, heart, kidneys and 
liver and 11.9% average CoV for lungs, pancreas and spleen.  (Note that we corrected 
the published calculations of standard deviations to the unbiased estimate using divisor 
= n-1.) Our own preliminary animal data had an average CoV of 24.4%. This suggests 
that mean organ values could be estimated with 95% confidence to within +/- 16% 
from a sample of size 10, and within +/- 11% from a sample of size 20. 
 
14.3 
Randomization of the sequence of studies will not be performed because of our 
objective to perform both studies on the same day; the [11C-methyl]-L- methionine 
study must be performed first because 11-C has the shorter physical half- life (20 
minutes vs. 110 min for 18-F). A 3 or more hour interval will separate the [11C- 
methyl]-L- methionine and 3-[18F]-FACBC studies to allow for near complete 11-C 
decay. 
 
14.4 
Data may be compared to FDG scans, when available. 
 
15.0 
SUBJECT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.1 
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. 


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IRB Number: 03-028 A(11) 
Approval date: 22-Sep-2017 
 
 
 
 
During the registration process registering individuals will be required to complete a 
protocol specific Eligibility Checklist. 
 
 
All participants must be registered through the Protocol Participant Registration (PPR) 
Office at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through 
Friday from 8:30am – 5:30pm at 646-735-8000. The PPR fax numbers are (646) 735- 
0008 and (646) 735-0003. Registrations can be phoned in or faxed. The completed 
signature page of the written consent/verbal script and a completed Eligibility Checklist 
must be faxed to PPR. 
 
15.2 
RANDOMIZATION 
Randomization of the sequence of studies will not be performed because of our 
objective to perform both studies on the same day; the [11C-methyl]-L- 
methionine study must be performed first because 11-C has the shorter physical 
half- life (20 minutes vs. 110 min for 18-F). A 3 or more hour interval will separate 
the [11C- methyl]-L- methionine and 3-[18F]-FACBC studies to allow for near 
complete 11-C decay. 
16.1 
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 coordinate 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. 
 
16.2 
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. 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
 
17.1 
Privacy 
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 


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Memorial Sloan Kettering Cancer Center 
IRB Number: 03-028 A(11) 
Approval date: 22-Sep-2017 
 
 
 
 
Authorization form must be completed by the Principal Investigator and approved 
by the IRB and Privacy Board. 
18.1 
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 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. 


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IRB Number: 03-028 A(11) 
Approval date: 22-Sep-2017 
 
 
 
 
19.1 
Reference(s) 
 
1. 
Patronas, N.J., G. Di Chiro, R.A. Brooks, and et al. 1982. Work in progress: [18F] 
fluorodeoxyglucose and positron emission tomography in the evaluation of radiation 
necrosis of the brain. Radiology 144:885-9. 
 
2. 
Di Chiro, G., R.L. DeLaPaz, R.A. Brooks, and e. al. 1982. Glucose utilization of 
cerebral gliomas measured by[18F]fluorodeoxyglucose and positron emission 
tomography.Neurology 32:1323-9. 
 
3. 
Doyle, W.K., T.F. Budinger, P.E. Valk, V.A. Levin, et al. 1987. Differentiation of 
cerebral radiation necrosis from tumor recurrence by [18F]FDG and 82Rb positron 
emission tomography. J Comput Assist Tomogr 11:563-70. 
 
4. 
Delattre, J.Y., Z. Fuks, G. Krol, D.A. Rottenberg, et al. 1988. Cerebral necrosis 
following neutron radiation 
 
5. 
Ogawa, T., K. Uemura, I. Kanno, and e. al. 1988. Delayed radiation necrosis of brain 
evaluated positron emission tomography. Tohoku J of Exper Med 155:247-60. 
 
6. 
Di Chiro, G., E. O ldfield, D.C. Wright, and e. al. 1988. Cerebral necrosis after 
radiotherapy and/or intraarterial chemotherapy for brain tumors: PET and 
neuropathologic studies. Amer J of Roentgenology 150:189-97. 
 
7. 
Lilja, A., K. Bergstrom, and P. Hartvig. 1985. Dynamic study of supratentorial 
gliomas with L- methyl-11C- methionine and positron emission tomography. Amer J 
Neuroradiology 6:505-14. 
 
8. 
Ericson K, Lilja A, Bergstrom M, Collins VP, Eriksson L, Ehrin E, von Holst H, 
Lundqvist H, Langsrom B B, Mosskin MP. Positron emission tomography with [11C] 
methyl- L-methionine, [11C]D- glucose, and [68Ga] EDTA in supratentorial tumors. J 
Comput Assist Tomogr., 1985 Jul;9(4):683-689. 
 
9. 
Derlon, J.M., C. Bourdet, P. Bustany, and e. al. 1989. 11C-L- methionine uptake in 
gliomas. Neurosurg 25:720-8. 
 
10. 
Kameyama, M., R. Shirane, J. Itoh, and e. al. 1990. The accumulation of 11C- 
methionine in cerebral glioma patients studied with PET. Acta Neurochirurgica 
104:8-12. 
 
11. 
Shoup TM, O lson J, Hoffman JM, Votaw J, Eshima D, Eshima L, Camp VM, Stabin 
M, Votaw D, Goodman MM.  Synthesis and evaluation of [18F]1-amino-3- 
fluorocyclobutane-1-carboxylic acid to image brain tumors. J Nucl Med 40: 331-338, 
1999. 
 
12. 
Comar D., Carton J.C., Maziere M. and Marazano C. Labelling and metabolism of 
methionine- methyl- 11 C. Eur J Nucl Med. 1976; 1(1): 11-14. 


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IRB Number: 03-028 A(11) 
Approval date: 22-Sep-2017 
 
 
 
 
13. 
Stabin MG, MIRDOSE: Personal computer software package for internal dose 
assessment in nuclear medicine, J.Nucl.Med. 1996; 37: 538-546. 
 
14. 
Loevinger R, Budinger T, Watson E, MIRD primer for absorbed dose calculations. 
New York, Society of Nuclear Medicine, 1988. 
 
15. 
Cloutier R, Smith S, Watson E, Synder W and Warner G, Dose to the fetus from 
radionuclides in the bladder. Health Phys. 1973; 25: 147-161. 
 
16. 
Deloar HM, Fujiwara T, Nakamura T, Itoh M, Imai D, Miyake M, Watanuki S. 
Estimation of internal absorbed dose of L-[methyl-11C]methionine using whole-body 
positron emission tomography. Eur J Nucl Med 25: 629-633, 1998. 
 
17. 
Mejia AA, Nakamura T, Masatoshi I, Hatazawa J, Masaki M, Watanuki S; Estimation 
of absorbed doses in humans due to intravenous administration of fluorine-18- 
fluorodeoxyglucose in PET studies. J Nucl Med 1991; 32:699-706. 
 
20.0 
APPENDICE(S) 
 
Appendix A. Radiopharmaceutical Preparation of [11C- methyl]-L- methionine and 3- 
[18F]-FACBC