Clinical trial NCT02016872
Conditions: Non-Small-Cell-Lung Cancer (NSCLC)
Keywords: PET/CT 18F-FMISO tumor hypoxia 13-186
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2013-12-16; Completion date: 2024-07-08
Enrollment: 25 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to help researchers investigate if a new imaging agent named 18F-FMISO can predict if patients with lung cancer will respond to standard therapy, as well as whether disease will reoccur in the future. The study will also investigate whether a 18F-FDG PET scan in the middle of radiation treatment can predict if lung cancer will respond to standard therapy. Information obtained from this study may help doctors design future studies in which they may target tumor areas that do not respond to therapy or may likely reoccur in the future.

Detailed description:

Arms: arm 1: All enrolled patients will undergo a baseline 18F-FDG PET scan as part of their standard clinical treatment for NSCLC. Dynamic 18F-FMISO PET scans will be performed on one of the GE PET/CT scanners in 3D mode, at least one day after the baseline 18F-FDG PET scan. The dynamic baseline 18F-FMISO studies may precede the 18F-FDG study if the patient had a CT or PET/CT scan within the last 30 days that would permit the investigators to localize the tumor of interest during the 18F-FMISO study. In a group of 5 patients, the feasibility of simultaneous imaging of 18F-FMISO and 18F-FDG will be assessed. The patient will have an IV line placed for radiotracer injection and for venous blood sampling. All dynamic PET scans will be performed over one PET FOV centered at the lesion position. The 18F-FDG mid-treatment PET/CT scan will be performed over only one bed position.
Interventions: intervention 1: 18F-FMISO intervention 2: PET/CT
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 13-186 A(7) 
Approval date: 22-Dec-2023 
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MSK PROTOCOL COVER SHEET 
Prognostic Value of Tumor Hypoxia, as Measured by 18F-FMISO Breath Hold PET/CT, in 
Non-Small-Cell-Lung Cancer (NSCLC) Patients 
 
Principal Investigator/Department: Jacob Shin, MD in the Department of Radiation Oncology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


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IRB Number: 13-186 A(7) 
Approval date: 22-Dec-2023 
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Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA .................................................................................. 4 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .......................................................................................... 6 
3.0 
BACKGROUND AND RATIONALE ................................................................................................... 7 
3.1 
18F-FDG PET/CT ............................................................................................................................... 7 
3.2 
Hypoxia ................................................................................................................................................. 8 
3.3 
18F-FMISO PET Scan and Tumor Hypoxia ......................................................................................... 8 
3.6 Correction for Respiratory Motion Artifacts: Deep-Inspiration-Breath-Hold (DIBH) PET/CT .............. 11 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ..................................................................... 11 
4.1 
Design ................................................................................................................................................. 11 
4.2 
Intervention ......................................................................................................................................... 12 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ....................................................................................... 12 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ...................................................................................... 12 
6.1 
Subject Inclusion Criteria.................................................................................................................... 12 
6.2 
Subject Exclusion Criteria .................................................................................................................. 13 
7.0 
Recruitment Plan with limited waiver of authorization .................................................................... 13 
8.0 
PRETREATMENT EVALUATION ................................................................................................... 14 
9.0 
TREATMENT/INTERVENTION PLAN ........................................................................................... 14 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION .......................................................... 17 
11.0 
TOXICITIES/SIDE EFFECTS ........................................................................................................... 19 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT .............................. 26 
13.0 
CRITERIA FOR REMOVAL FROM STUDY .................................................................................. 26 
14.0 
BIOSTATISTICS .................................................................................................................................. 26 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES ... 27 
15.1 
Research Participant Registration ....................................................................................................... 27 
15.2 
Randomization .................................................................................................................................... 28 
16.0 
DATA MANAGEMENT ISSUES ....................................................................................................... 28 
16.1 
Quality Assurance ............................................................................................................................... 28 
16.2 
Data and Safety Monitoring ................................................................................................................ 29 
17.0 
PROTECTION OF HUMAN SUBJECTS .......................................................................................... 29 
17.1 
Privacy ................................................................................................................................................ 29 


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IRB Number: 13-186 A(7) 
Approval date: 22-Dec-2023 
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17.2 
Serious Adverse Event (SAE) Reporting ............................................................................................ 30 
17.2.1 
Not Applicable ............................................................................................................................ 31 
18.0 
INFORMED CONSENT PROCEDURES .......................................................................................... 31 
19.0 
REFERENCES ...................................................................................................................................... 32 
20.0 
APPENDICES ....................................................................................................................................... 36 


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IRB Number: 13-186 A(7) 
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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
This is an NCI funded (U01CA157442-01A1) study to assess the prognostic value of fluorine-18- 
labeled fluoro-misonidazole (18F-FMISO), a hypoxia radiotracer, in patients with non-small cell lung 
cancer (NSCLC) who are treated with definitive conventionally fractionated radiation therapy (RT), 
neoadjuvant chemotherapy, or chemo-RT. The secondary goal will be to assess the predictive value of 18F- 
FDG, a metabolic rate radiotracer, in a second group. Please note that all patients entered on this 
protocol will undergo the standard of care treatment for NSCLC. The information obtained from the 
use of investigational 18F-FDG and 18F-FMISO PET scans will NOT be used to manage patients’ 
treatment on this protocol. 
Schema: 
There are two groups currently active in this protocol. Group 1 includes a mid-treatment FMISO PET 
scan and FDG PET scan. Group 2 includes a sequential injection of 18F-FMISO and 18F-FDG. Both 
groups will have completed a routine pre-treatment FB and breath-hold 18F-FDG PET/CT and pre- 
treatment 18F-FMISO PET Scan. 
• Group 1: Perform a routine pre-treatment free-breathing (FB) and breath-hold (for only one PET 
Field of View, i.e. an additional ~10 min of PET/CT imaging) 18F-FDG PET/CT. If the patient is 
planned to receive radiotherapy, the FB PET/CT scan will be used for RT planning. 
• Group 2: Perform a routine pre-treatment free-breathing (FB) 18F-FDG PET/CT. If the patient is 
planned to receive radiotherapy, the FB PET/CT scan will be used to RT planning. 
• Both groups with perform a pre-treatment dynamic 18F-FMISO PET scan (18F-FMISO1). This scan 
will occur at least one day after the baseline 18F-FDG PET/CT scan, but prior to initiation of therapy. 
A baseline 18F-FDG PET/CT scan may be acceptable provided it is not earlier than one month 
prior to the 18F-FMISO study and will assist to define the field of view of the dynamic 18F-FMISO 
PET scan. If a CT is available to allow definition of the tumor region, then the 18F-FMISO may be 
performed before the FDG PET scan. Dynamic 18F-FMISO PET images will be corrected for 
breathing-induced artifacts allowing kinetic analysis to be performed for both the motion-corrected 
and the free-breathing dynamic PET image sets. The degree of hypoxia within the tumor volume 
will be estimated by the magnitude of the 18F-FMISO irreversible trapping rate constant. 
• Group 1 : 18F-FMISO2/FDG mid-treatment PET/CT: Perform a mid-treatment dynamic 18F- 
FMISO (FMISO2) PET/CT (following the same protocol as for the baseline FMISO) scan in a 
group of twenty five patients, undergoing RT or concurrent chemo-RT. This scan will occur two 
weeks +/- 4 days after the start of radiotherapy or the radiation portion of combined chemo- 
radiation (Diagram 1). 
 
• Perform a mid-treatment 18F-FDG PET/CT scan in a group of twenty five patients, undergoing RT 
or concurrent chemo-RT. This scan will occur two to three weeks +/- 4 days after start of treatment 
of radiotherapy or the radiation portion of combined chemo-radiation.18F-FDG PET/CT scans will 
be performed in both Free-Breathing (FB) and Breath-Hold (BH) modes. The predictive value of 
18F-FDG, based on the change in lesion SUVpeak between baseline and the 3-week mid-treatment 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-186 A(7) 
Approval date: 22-Dec-2023 
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scan and following the PERCIST criteria, will be assessed using both the FB, and the BH, image 
sets independently. Results deduced from the FB and BH data sets will be compared and correlated 
with outcome. 
• Group 2: Combined 18F-FMISO/18F-FDG baseline PET/CT: In a group of 5 patients, two PET 
radiotracers 18F-FMISO and 18F-FDG will be injected sequentially into the patient. Since all PET 
radiotracers emit the same 511 keV coincidence photons, it is not possible to discriminate events 
from these different radiotracers. However, by conducting a dynamic PET/CT scan with staggered 
18F-FMISO and 18F-FDG injections (45min +/- 15min apart), the kinetic profiles should provide 
sufficient information to allow signals from the two radiotracers to be clearly separated. This 
sequential 18F-FMISO / 18F-FDG study will be performed at least one day after the sole FMISO1 
radiotracer baseline PET/CT scan, and prior to the initiation of therapy. The 18F-FMISO and 18F- 
FDG individual signals will be deduced from the combined dynamic PET images by means of 
kinetic modeling, and the corresponding radiotracers entrapments within the tumor will be 
determined. The accuracy of the 18F-FMISO signal extraction from the combined one in the staggered 
18F-FMISO/18F-FDG dynamic PET/CT study will be assessed by comparison to that deduced from 
the sole FMISO1 study (Diagram 2). 
 
 
 
 
Diagram 1. Combined 18F-FMISO/18F-FDG baseline PET/CT 


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IRB Number: 13-186 A(7) 
Approval date: 22-Dec-2023 
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Diagram 2. Group 2: Sequential FDG and FMISO treatment group 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
The primary objectives of this study are: 
• To correlate the presence and extent of hypoxia, as defined by 18F-FMISO FB and BH PET/CT 
at baseline with 3-year progression-free survival (PFS) and overall survival (OS). 
 
• To assess the predictive value of 18F-FMISO PET/CT in lung cancer patients undergoing 
radiotherapy or concurrent chemoradiotherapy, as measured by Breath-Hold (BH) and Free- 
Breathing (FB) PET/CT images, and to determine whether BH PET/CT provides greater 
predictive capability than Free-Breathing (FB) PET/CT. 
The secondary objective of this study is: 
 
• To assess the predictive value of 18F-FDG PET/CT in a group of twenty five lung cancer 
patients undergoing radiotherapy or concurrent chemoradiotherapy, as measured by Breath- 
Hold (BH) and Free-Breathing (FB) PET/CT images, and to determine whether BH PET/CT 
provides greater predictive capability than Free-Breathing (FB) PET/CT. 


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• 
To assess the feasibility of simultaneous 18F-FDG and 18F-FMISO PET dynamic acquisitions 
in a group of 5 patients undergoing radiotherapy or concurrent chemoradiotherapy. If 
successful, our approach would allow multi-radiotracer PET exams on the same day reducing 
the need for extra patient visits. For the patients who will undergo the dual FMISO/FDG study, 
the mid-treatment FMISO will be optional. 
 
3.0 
BACKGROUND AND RATIONALE 
3.1 
18F-FDG PET/CT 
 
18F-FDG PET is a non-invasive molecular imaging tool that has been shown to have a major impact on 
the diagnosis and staging of NSCLC, as well as in treatment planning of radiotherapy and detection of 
recurrent disease (1-4). Its prognostic and predictive values in NSCLC have been well demonstrated 
(5) 
 
In a pilot study that included 15 patients, a reduction in 18F-FDG uptake of more than 50% between 
pre- and post- induction chemotherapy in the primary tumor or mediastinal clearance was shown to 
be a better predictor of long-term survival (6) compared with the standard WHO criteria used for 
response assessment on CT. In another multi-center study that evaluated 18F-FDG-PET before and 
after 1 and 3 cycles of induction chemotherapy the residual metabolic rate of glucose after completion 
of induction chemotherapy appeared to be the most prognostic factor (7). Its predictive value with 
respect to therapy outcome of combined chemo-radio therapy has also been demonstrated (8-10). 
Currently, no early markers of tumor response to radiation therapy are in existence or in clinical use. 
While FDG-PET has become a standard modality for staging and re-staging of NSCLC, its value as 
an early response marker during radiation therapy remains unclear. The University of Michigan tested 
the value of a mid-treatment FDG-PET scan at 45 Gy in 15 patients (11). The qualitative response 
during RT correlated with the overall response post-RT. However, the later during the treatment 
course the PET scan is performed, the lesser are the chances of making adjustments to the initial first- 
line treatment, as the majority of the RT dose is already delivered at 45 Gy. Therefore, we are 
planning to perform the FDG-PET scan at an earlier time point of 3 weeks at a dose of approximately 
30 Gy. This will provide the basis for early tumor assessment and adaptive radiation therapy 
strategies that would take into account an early tumor response. It would allow stratification of 
patients into favorable and unfavorable responders and the development of individually tailored 
strategies for these patients. 
 
Consequently, 18F-FDG-PET can form the basis for clinical trials evaluating the feasibility of adopting 
therapy based on response assessment (12-15). 
Due to patient breathing, FDG PET quantitation may become susceptible to breathing-induced 
uncertainties, which may reduce the prognostic and predictive values of FDG-PET. Breath-Hold 
PET/CT acquisition has been shown to improve the accuracy of PET quantitation. In contrast to the 
study by Kong et al. (11), we will therefore measure the prognostic and predictive values of FDG PET 
using BH PET data, and compare those with results deduced from the free-breathing data sets. Due to 
the improved accuracy of BH-PET quantitation, we expect BH data would yield improved prognostic 
values over those of the FB PET. 


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IRB Number: 13-186 A(7) 
Approval date: 22-Dec-2023 
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3.2 
Hypoxia 
 
Hypoxia is a characteristic feature of malignant tumors that has been well established (16-22) . Unlike 
healthy tissues, tumors often grow at a rate that outgrows their blood supply resulting in the emergence of 
regions of hypoxia. Immunohistochemical studies have shown nests of hypoxic cells of up to several 
hundred micrometers in diameter, located at poorly perfused locations within the tumor (23-25). 
Hypoxia can create selective pressures that render the tumor more aggressive and radioresistant, and 
has been shown to exhibit an increased likelihood of locoregional recurrence, propensity for metastasis, 
and poor overall outcome. With invasive measurements, a hypoxia fraction HF2.5 (percentage of 
measurements <2.5 mmHg) was shown to be the most predictive factor for survival in head & neck 
cancer (HNC), with a threshold HF2.5 of 20% [17]. In NSCLC, 62% of patients exhibited a HF2.5 < 
20% (26). 
 
Locoregional control in non-surgically treated NSCLC patients continues to be a major challenge. 
Locally-advanced NSCLC patients currently experience freedom from local progression at 3 years 
(FFLP, defined as intrathoracic tumor progression by World Health Organization criteria) of only 38% 
and locoregional control (LRC, a stricter definition that requires at least a partial response prior to 
progression) of 14%, with a 5-year overall survival of approximately 20%, as it was recently 
demonstrated in a comprehensive review of seven RTOG trials (27). This may at least in part be due 
to the often large tumor size and significant hypoxia levels in these tumors. PET is a noninvasive 
imaging modality with the potential to identify tumor hypoxia at both global and local levels through 
the use of hypoxia targeting molecules. If these hypoxic regions are identified, this will lay the 
foundation for future studies targeting these hypoxic sub-regions and/or altering treatment regimen, 
with the ultimate goal to improve the treatment outcome of patients with NSCLC. We and others have 
previously shown that dose escalation can be successfully given to patients with stage III NSCLC to a 
maximum tolerated dose (MTD) of 84 Gy (28). This resulted in a promising 2-year local control rate 
of 52%. RTOG 0117, a phase I/II dose escalation study in patients treated with concurrent 
chemoradiation, found the MTD to be 74 Gy (29). A pooled analysis of seven RTOG studies of 
chemoradiation for locally advanced NSCLC found that a 1-Gy increase in biologically effective dose 
resulted in an approximately 4% relative improvement in survival and a 3% relative improvement in 
locoregional control (30). Currently, the standard dose for concurrent chemoradiation therapy is 60 Gy. 
While a recent phase III study (RTOG 0617) appeared to be unsuccessful when escalating the dose to 
the entire tumor volume to 74 Gy (31), it remains unknown whether escalating the dose to 
radioresistant tumor subvolumes would not result in better tumor control. Therefore, identifying such 
subvolumes may provide the basis to a more intelligent dose escalation approach in order to improve 
the dismal outcomes in stage III NSCLC. 
 
3.3 
18F-FMISO PET Scan and Tumor Hypoxia 
 
Positron emission tomography with 18F-Fluoromisonidazole (18F-FMISO PET) is a non-invasive 
imaging technique that was shown to be clinically feasible for detecting tumor hypoxia in NSCLC (32, 
33). Patients will be given the option to participate in a research study that aims to investigate the 
prevalence of hypoxia (as determined by 18F-FMISO PET) in this patient population, and to assess the 
reproducibility and prognostic value of 18F-FMISO dynamic PET (dynPET) images in NSCLC patients 
prior to standard treatment for their lung cancer. Tumor hypoxia is an independent predictor of poor 


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IRB Number: 13-186 A(7) 
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prognosis in several types of cancer, including NSCLC. Hypoxia imaging may be of particular interest 
in NSCLC, because it is relatively common in lung cancer, and because the outcome for hypoxic tumors 
may potentially be improved with more aggressive chemotherapy or radiotherapy, or hypoxia-directed 
treatments such as the administration of hypoxia activated prodrugs (34, 35) or carbogen breathing 
(95% oxygen, 5% carbon dioxide) (36). 18F-FMISO PET has been shown to correlate with hypoxia and 
treatment outcome in NSCLC (32, 37). Previous study used either qualitative analysis of the dynamic 
FMISO time activity curves (38) or quantitative analysis of late static FMISO images (37) to identify 
hypoxia. 
The optimal method to quantitate hypoxia using 18F-FMISO is to perform compartmental analysis of 
the dynPET images (39-41). This is a method which uses kinetic information from dynamic scans to 
assess the rate of uptake and entrapment within the hypoxic tumor tissue. However, compartmental 
analysis is not meaningful on standard clinical PET images of the lung because of respiratory motion 
during the PET acquisition. Our group at MSKCC has developed a technique for Breath-Hold (BH) 
PET/CT imaging. During BH PET/CT, patients are asked to hold the breath for as long as possible, and 
data are acquired only during the time of the BH, using an in-house respiratory tracking device to 
monitor patient breathing motion (42). PET emission data will be acquired only while the patient is 
holding the breath as monitored by an external camera and chest sensor. This process will be repeated 
until a total of 3 min of BH PET data (equivalent to clinical setup) are acquired. We now propose a 
novel technique to acquire motion-free 18F-FMISO dynPET images of lung (one 15 cm field of view) 
to make accurate compartment analysis, and thus quantification of tissue hypoxia, possible. We shall 
acquire clinical 18F-FMISO dynPET images in Free-Breathing (FB) with the list mode (LM) option. 
During the dynamic PET study, the patient’s breathing signal will be recorded simultaneously using an 
in-house developed tracking software assisted by a video camera. The camera is used to monitor the 
motion of fiducial markers positioned on the patient’s abdomen. The patient’s breathing signal will be 
correlated to the PET data on an event-by-event basis and then only those corresponding to end- 
expiration will be selected for the final PET images, thus resulting in motion-free images. Incorporating 
all the PET events from the same dynamic PET study results in the FB dynamic PET data set. 
In PET/CT, CT images are used to correct for attenuation in the PET images. Spatial matching between 
PET and CT images is therefore crucial. Therefore, CT images at breathing phases matching those of 
the PET images will be acquired. PET data will be corrected for attenuation using the phase-matched 
CT images. 
The value of 18F-FMISO-PET as an early response marker during radiation therapy is still unknown. 
In a study in 20 patients with head and neck cancer who underwent baseline and mid-treatment FMISO 
imaging, 90% of patients showed complete resolution of 18F-FMISO uptake in the mid-treatment scan, 
suggesting tumor re-oxygenation (43). In the current study, we will assess the predictive value of 18F- 
FMISO at 2 weeks +/4 days post-initiation of therapy (~ at a dose of 20Gy). This will allow 
identification of persistent radioresistant tumor sub-volumes. These data may provide the basis for 
future response adaptive radiation therapy strategies. For instance, patients with persistent hypoxia, if 
prognostic of poor outcome, may in a future studies be selected for a site directed additional radiation 
boost. 
 
In this protocol, both 18F-FMISO and mid-treatment 18F-FDG imaging shall be used for exploratory 
research purposes only; the image findings and results will not be used to change patient management. 
MSKCC holds an IND for the use of 18F-FMISO under IRB protocol #04-070 (P.I. Dr. Nancy Lee). 


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IRB Number: 13-186 A(7) 
Approval date: 22-Dec-2023 
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This protocol shall use 18F-FMISO under cross-file with IND 115764, since the radiolabeling chemistry 
and dosage shall be identical to protocol IRB #04-070. 
 
 
3.4 Simultaneous imaging of tumor hypoxia and tumor metabolism 
Imaging hypoxia and metabolism simultaneously may provide a new understanding of the role of the 
tumor microenvironment; in particular the interplay between hypoxia (defined by 18FMISO) and tumor 
cell metabolism (defined by 18FDG). 
18F-FMISO and 18FDG have been shown to be important prognostic and predictive biomarkers in 
patients undergoing CRT [59, 60]. Identifying simultaneously hypoxic and metabolically active sub- 
regions within the tumor is a more coherent measurement of the tumor microenvironments than co- 
registering images acquired in different imaging sessions where temporal changes in the biology and 
inaccuracies in the image registration curtail the integrity of the data. Previous studies have 
demonstrated both the feasibility and potential for simultaneous assessment of two physiological 
processes (mainly in brain) by exploiting temporal [61] kinetic, or daughter outputs (positron vs 
positron+cascade ) (44) differences between radiotracers. 
In this protocol, we are going to apply a new method to obtain the information from two F-18 based 
PET radiotracers (18F-FMISO and 18FDG) in a single PET/CT acquisition. We have developed a 
preliminary means of decoupling the individual signals with the ultimate goal to use the combined 
hypoxia/metabolic rate map to guide and adapt CRT, and monitor response in a larger cohort of patients 
with NSCLC and other malignancies. In preliminary studies, we have successfully established 
methodology and validated that in both mathematical simulations and animal models, for achieving 
this objective, and propose to apply this methodology to patients receiving sequential 18F-FMISO and 
FDG dynamic PET exams in this study. We propose to conduct compartmental analysis from a single 
dynamic 18FMISO and 18FDG PET acquisition in which 18FMISO is injected concurrently with the 
start of the dynamic PET acquisition, followed by an injection of 18FDG about 45 min +/- 15 min later. 
We hypothesize that simultaneous 18FMISO and 18FDG PET imaging will result in prognostic and 
predictive values that are superior to those achieved when imaging is performed separately for each 
radiotracer (i.e. in 2 scanning sessions, days apart). We believe this enhancement will be due to (1) 
exact co-localization of the 2 markers (no co-registration necessary), and (2) absence of inter-scan 
transient biologic changes. We believe this method will lay the foundation for future studies using dual 
PET radiotracers in patients with NSCLC and other malignancies, and may have potential implications 
for dose painting strategies in radiotherapy, adaptive CRT, and assessing response to treatment. If 
clinically feasible, comparison of the prognostic and predictive values of combined 18F-FMISO/18F- 
FDG with those of each of the two radiotracers (when imaged separately) shall be the subject of a future 
investigation in a larger cohort of lung patients. 
 
 
3.5 Respiratory Motion in PET/CT imaging of the thorax 
Patient’s respiratory motion during PET/CT imaging results in artifacts in the PET/CT images due to 
internal organ motion. In CT images, breathing-induced artifacts are mainly due to the dynamic 
interaction between transaxial image acquisition and the asynchronous motion of tumor and normal 
tissue (45). Commonly observed artifacts include distortion of the dome of the liver at the lung- 
diaphragm interface, splitting of a tumor into multiple distinct parts, out-of-order shuffling of the 
transaxial slices, and creation of discontinuities in the diaphragm/lung interface (45). In PET, due to 


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the long acquisition time per bed position (3 to 7 min), PET images are then time-averaged over many 
breathing cycles (average breathing period is 5 seconds). This results in the blurring of the target 
volume (42, 46, 47), and reduces the apparent radiotracer uptake (46, 48). 
 
In hybrid PET/CT, respiratory motion can result in hybrid motion artifacts, primarily due to the 
temporal mis-match between PET images and the corresponding CT-based attenuation map. A 
common artifact due to the tempo-spatial mis-match between PET and CT is the mis-localization of 
lesions at the border of two organs (42, 49). The tempo-spatial mismatch between PET and CT images 
can also result in an increased uncertainty in the apparent tumor SUV due to the use of a non-spatially 
matching CT image set to correct for attenuation in the PET images. Erdi and co-workers showed 
dependence of the measured tumor SUV on the breathing phase at which CT images were acquired at. 
 
3.6 Correction for Respiratory Motion Artifacts: Deep-Inspiration-Breath-Hold (DIBH) 
PET/CT 
 
We have recently developed a novel technique to correct for breathing artifacts in PET/CT images, the 
Deep-Inspiration-Breath-Hold (DIBH) acquisition(42). We believe DIBH is the most pragmatic and 
robust approach to eliminate misregistration of PET and CT data. In this approach, the patient is 
instructed to hold the breath during CT acquisition. The amplitude at which the hold (HA) period occurs 
is identified using a respiratory tracking system. During PET acquisition, the patient is then instructed 
to hold the breath at the same (HA), over subsequent periods. PET data will be acquired only while the 
patient is holding the breath as monitored by an external camera and chest sensor. This will repeated 
till a total of 3min of BH PET data are acquired. Finally, PET data corresponding to the hold periods 
are summed into one data set, and then reconstructed using the corresponding breath-hold CT image 
set. With DIBH PET/CT (as compared to nonrespiratory motion-corrected PET/CT) we observed as 
much as an 83% increase in lesion SUV, and as much as 50% improvement in spatial matching between 
PET and CT(42). DIBH PET/CT had the advantage of reducing misregistration, as both the CT and the 
PET components were acquired in the same respiratory phase. This was particularly useful for 
distinguishing between pulmonary and extrapulmonary lesions in the chest wall or mediastinum. 
Additionally, a small nodule that was not seen on clinical PET/CT showed mild 18F-FDG uptake on 
BH PET/CT; this was an additional site of metastasis in a patient with lymphangitic spread. DIBH- 
PET also results in an improved signal-to-noise ratio, which can yield increasing lesion detectability. 
In CT, DIBH imaging also resulted in detection of 2.2 additional nodules on average per patient, 
especially when those nodules were smaller than 0.5 cm(50). DIBH CT also allowed more precise 
localization and characterization of pulmonary lesions than non-DIBH CT(42, 50). 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
This is a single-institution exploratory study evaluating the prognostic and predictive significance and 
reproducibility of tumor hypoxia as imaged by 18F-FMISO PET, in NSCLC patients before receiving 
any treatments for their disease. In a sub-group of these patients, we will assess the predictive value of 
18F-FDG PET/CT as well. Moreover, in a sub-group of five patients, we will assess the feasibility of 
simultaneous 18F-FMISO/18F-FDG acquisitions. Patients will be identified in thoracic oncology, 
radiation oncology, or radiology departments at the time of their planned diagnostic imaging studies. 


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We will also evaluate the pharmacokinetic properties of 18F-FMISO during the imaging studies. 
Moreover, we will evaluate the significance of breath hold (BH) imaging over standard techniques in 
both18F-FDG PET/CT and 18F-FMISO PET/CT image sets in patients from Group 1, as outlined in 
Sections 9.1 and 9.2. Patients will be identified and consented prior to their baseline 18F-FDG-PET/CT. 
A total of 25 patients will be accrued for this study over a 3 year period; 10 patients who are receiving 
RT or concurrent chemo RT and 16 patients who are receiving neoadjuvant chemotherapy. The group 
of 10 patients receiving RT or concurrent chemo-RT will receive an additional repeat 18F-FDG PET/CT 
scan at mid-treatment. 
4.2 
Intervention 
All enrolled patients will undergo a baseline 18F-FDG PET scan as part of their standard clinical 
treatment for NSCLC. Dynamic 18F-FMISO PET scans will be performed on one of the GE PET/CT 
scanners in 3D mode, at least one day after the baseline 18F-FDG PET scan. The dynamic baseline 18F- 
FMISO studies may precede the 18F-FDG study if the patient had a CT or PET/CT scan within the last 
30 days that would permit the investigators to localize the tumor of interest during the 18F-FMISO 
study. In a group of 5 patients, the feasibility of simultaneous imaging of 18F-FMISO and 18F-FDG will 
be assessed. The patient will have an IV line placed for radiotracer injection and for venous blood 
sampling. All dynamic PET scans will be performed over one PET FOV centered at the lesion position. 
The 18F-FDG mid-treatment PET/CT scan will be performed over only one bed position at the times 
identified in section 1.0. 
The studies outlined in Section 9.0 are the intervention. These research study results will not impact 
clinical care which will be left to the discretion of the treating physician. Patients will be followed 
with CT scans of the chest every 3-4 months in the first three years as per standard clinical care. 
Available data will be used for radiologic progression of disease and survival. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
F-18 labeled F-misonidazole is prepared and tested for quality assurance in this study at MSKCC or 
by an equivalent qualified supplier. The radiopharmaceutical is being utilized in this protocol under a 
MSKCC IND. Bio-distribution data on 18F-MISO are summarized in section 11.2.3. 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
6.1 
Subject Inclusion Criteria 
• Pathologic confirmation of NSCLC at MSKCC 
• No prior treatment for this diagnosis of NSCLC 
• Patient to be treated with neoadjuvant chemotherapy or patient to be treated with 
definitive RT, sequential chemo-RT, or concurrent chemo-RT (minimum dose of 50 
Gy in 25 fractions) 
• Tumor must measure ≥ 2cm on CT 
• Age ≥ 18 years 
• Ability to hold the breath for 10 seconds 
• Karnofsky performance status ≥ 70% 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-186 A(7) 
Approval date: 22-Dec-2023 
Page 13 of 36 
 
 
• Women of childbearing age must have a negative blood pregnancy test 
 
6.2 
Subject Exclusion Criteria 
• Women who are pregnant or breast-feeding 
• Severe diabetes (fasting Blood Glucose > 200 mg/dl) 
 
 
7.0 
Recruitment Plan with limited waiver of authorization 
Potential research subjects will be identified by a member of the patient’s treatment team, the protocol 
investigator, or research team at Memorial Sloan-Kettering Cancer center (MSKCC). If the 
investigator is a member of the treatment team, s/he will screen their patient’s medical records for 
suitable research study participants and discuss the study and their potential for enrolling in the research 
study. Potential subjects contacted by their treatment physician will be referred to the 
investigator/research staff of the study. 
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. 
Patients who are receiving chemotherapy only will be identified when they are referred to Nuclear 
Medicine for their standard FDG PET scans. Patients receiving combined chemoradiotherapy will be 
identified by the treating Radiation Oncologist when they are assessed in the Radiation Oncology 
clinics. 
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. 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. For these reasons, we seek a 
(partial) limited waiver of authorization for the purposes of (1) reviewing medical records to identify 
potential research subjects and obtain information relevant to the enrollment process; (2) conversing 
with patients regarding possible enrollment; (3) handling of PHI contained within those records and 
provided by the potential subjects; and (4) maintaining information in a screening log of patients 
approached. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-186 A(7) 
Approval date: 22-Dec-2023 
Page 14 of 36 
 
 
As participating in this protocol is not intended to provide any clinical benefit to the patient, patients 
will receive a stipend for their time. At the completion of their study participation, patients will receive 
a check for up to $200, which is $100 per completed FMISO scan session. If the patient does not 
complete both scan sessions, the stipend which they receive will be prorated for the number of sessions 
completed. 
8.0 
PRETREATMENT EVALUATION 
Patients must have the following tests or procedures prior to receiving any protocol scans. 
• Histological confirmation of Non-Small Cell Lung Cancer at MSKCC 
• Review of medical history and current medications 
• Physical examination 
• Pregnancy test for women of childbearing potential 
• Standard clinical scans: 
o 
18F-FDG PET Scan performed at MSKCC 
o CT scan of the chest 
9.0 
TREATMENT/INTERVENTION PLAN 
Patients will be monitored by a member of the nuclear medicine staff before, during and through 
the completion of their imaging studies. 
9.1 
18F-FDG PET/CT: 
In patients who have consented to this study prior to their baseline 18F-FDG PET scan, 4D-CT (10 
mA)/free breathing PET and breath hold CT(10 mA)/PET images will be acquired over one field-of- 
view encompassing the lesion in the 18F-FDG PET/CT scan in order to assess the improvement in the 
prognostic value of 18F-FDG-PET/CT in lung cancer due to correction of breathing-induced artifacts 
in the PET/CT images. The PET/CT acquisition will be assisted by an in-house developed respiratory 
tracking software and video camera to monitor the patients breathing motion, and then correct for 
breathing–induced artifacts in the PET/CT images. The patient breathing during all phases of the study 
will be monitored and recorded by the respiratory tracking device. Such respiratory tracking allows 
events captured by the PET scanner to be associated with different phases of the respiratory cycle. The 
baseline and follow-up 18F-FDG PET/CT scans for each individual patient should be performed on the 
same PET/CT scanner for consistency purpose. For patients receiving radiation therapy or concurrent 
chemo-RT, this research procedure will immediately follow the standard radiotherapy 18F-FDG 
PET/CT simulation protocol, with the patient in treatment position. This group will also receive a mid- 
treatment 18F-FDG PET/CT scan which will occur three weeks +/- 4 days after start of treatment of 
radiotherapy or the radiation portion of combined chemo-radiation. This mid-treatment 18F-FDG 
PET/CT is investigational. Only patients in Group 1 will participate in BH scans. 
All research scans will be performed by the Nuclear Medicine team. For patients receiving radiation, 
all 18F-FDG PET/CT scans will be performed on the GE PET/CT scanner residing in the radiotherapy 
simulation suite. Otherwise, those scans will be performed on one of the GE PET/CT scanners residing 
in nuclear medicine. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-186 A(7) 
Approval date: 22-Dec-2023 
Page 15 of 36 
 
 
9.2 
18F-FMISO PET/CT Scan Protocol: 
The first 18F-FMISO PET/CT scan will be performed within 14 days (+/- 5 days) after the baseline 18F- 
FDG scan, and before starting therapy. Dynamic FMISO PET scans will be performed on one of the GE 
Discovery PET/CT scanners residing in the nuclear medicine department at MSKCC. The patient will be 
set up in treatment position with intra-venous lines for radiotracer injection and for venous blood 
sampling. One 370 MBq (10 mCi) +/- 10% dose of 18F-FMISO will be injected as a bolus, and the 
dynamic scan initiated coincident with the injection. 
Dynamic 18F-FMISO PET data will be acquired in List Mode and reconstructed in time frames that 
display the kinetics of tumor uptake. The total duration of the study is approximately 3 hours. The 
patient is injected in the PET scanning position on the couch and PET data acquired from 0-40 min. 
The patient is then allowed to return to the waiting room and rest. There are two further scan segments 
at approximately 90 min and 180 min post injection each of 10-minute duration. The total PET scan 
time within the 3 hour imaging session is therefore only 60 minutes. No further radioactivity will be 
injected for the 2nd and 3rd PET scan segments. In all three sessions of the dynamic PET study, the 
patient’s breathing signal will be recorded simultaneously using the in-house developed tracking 
described previously. The respiratory signal will be used to retrospectively identify those PET events 
that occurred at end-expiration. Those events will be selected retrospectively to generate a dynamic 
PET data set corresponding to end-expiration (BH-dyn PET), motion-free PET images. 
In each of the three dynamic sessions, a 4D-CT (10mA) scan and a BH-CT (10mA) scan (at end- 
expiration) of a 15cm segment of the body (the field of view of the PET scanner) will be performed 
with the tumor at the field center. These images will be used for both attenuation correction and 
registration of the serial image set, for the free-breathing and BH PET dynamic data sets respectively. 
To further facilitate patient image registration, external fiducial markers may be placed on the patient’s 
thorax. 
A second set of three dynamic 18F-FMISO scans will be performed following the same sequence as 
outlined above for the baseline dynamic 18F-FMISO study, at 2 to 3 weeks (+/- 4 days) post-initiation 
of therapy. 
To ensure patient safety, vital signs and toxicity assessments will be performed immediately after 
each scan session. Additionally, approximately 24 hours (or on the next business day) after the 
completion of each scan session, a toxicity assessment will be completed via a telephone followup. 
 
Only patients in Group 1 will participate in BH scans. 
 
9.3 
Pharmacokinetic Modeling of 18F-FMISO PET: 
The dynamic data of the 18F-FMISO radiotracer in the tumor must be supplemented by clearance data 
from the blood. Blood samples may be taken at pre-designated times during the 18F-FMISO PET scan. 
If the PET images contain the heart within the field of view, one IV blood sample (about 1-2 ml) will 
be drawn at 30-40 minutes post 18F-FMISO injection. If the heart is not within the PET FOV,a 
maximum of 9 IV blood samples (about 1-2 ml each) may be obtained at approximately the following 
time points: 1, 2, 3,4, 5, 15, 30, 90 and 180 minutes post injection. A separate IV line (other than the 
one used for FMISO injection) will be used to draw the blood. These samples will be weighed and 
counted for the purpose of determining the blood clearance kinetics and the tumor input function. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-186 A(7) 
Approval date: 22-Dec-2023 
Page 16 of 36 
 
 
1, 
Compartmental kinetic analysis of the dynamic 18F-FMISO PET images will be conducted using the 
blood clearance time activity curve as input function to the 18F-FMISO compartmental model. The 
kinetic rate constants k1, k2, and k3 (trapping rate) will be deduced. As a first approximation, hypoxic 
sub-regions within the tumor will be defined based on a k3 > 0.1. We will then re-assess this k3 
threshold based on results from the first 12 patients. 
The same kinetic analysis will be repeated for the 2nd baseline 18F-FMISO study. The kinetic rate 
constants from the first and second 18F-FMISO studies will be compared, as well as the geographic 
positions of the hypoxic sub-volumes within the tumor between the first and second scans. 
 
9.4 Simultaneous 18F-FDG/18F-FMISO PET/CT Scan Protocol: 
Simultaneous Dynamic PET 18FMISO/18FDG scan will be performed at least one day after the sole 
baseline 18FMISO PET/CT, but preceding chemo- or radiation therapies. Dynamic PET/CT data 
will be acquired over the same single FOV as for the sole baseline 18FMISO PET/CT described 
above. CT images will be acquired for PET attenuation correction purpose. Imaging will start 
simultaneously with the intravenous bolus injection of 18F-FMISO (8 mCi +/- 10%). PET data will 
be acquired in list mode (LM). The dynamic acquisition will last for up to a total of 120 min. 8 
mCi (+/- 10%) of 18FDG will be injected intravenously 45 min +/- 15 min after the 18F-FMISO 
injection, and without interruption of the dynamic PET acquisition. One additional 10 min dynamic 
PET scan will be performed at 180 min post-FMISO injection. If the patient cannot tolerate the 
length of the first imaging session, an additional 10 min dynamic PET scan may be performed at 
90 min +/- 10 min. Blood samples may be withdrawn following the same protocol as for the sole 
FMISO dynamic study described above. 
For each of the imaging sessions a 4DCT at 10mA and a CT-BH (40mA and 1-mA for the first 
session and the subsequent sessions respectively) will be performed for attenuation correction, 
 
All PET and CT data will be acquired and recorded in a secure patient database. During all imaging 
sessions, patients will be immobilized in RT alpha cradle if available and tolerable. 
 
9.5 Pharmacokinetic Modeling of Simultaneous 18F-FDG/18F-FMISO PET: 
We will perform compartmental analysis of the combined 18F-FMISO/18F-FDG tumor uptake 
profiles obtained from dynamic PET images. The individual 18F-FMISO and 18F-FDG input 
functions will be derived from the drawn blood samples during the dynamic PET study, using Thin 
Layer Chromatography (TLC), and based on methodology we have previously developed. We have 
previously shown the feasibility of this technique to uncouple8F based radiotracers, 18F-FMISO 
and 18F-FLT. We will use the same technique here to uncouple the FMISO/FDG fractions in the 
blood. The tumor combined FMISO/FDG Time Activity Curve (TAC), will be determined from 
the dynamic PET image set, and then the 18FMISO and 18FDG respective output functions will 
uncoupled from the combined TAC. Finally, compartmental analyis will be carried out for the 
FMISO and FDG respective output functions The kinetic parameters V 
k2, k3, and k4 (for 
18FDG) will be calculated for the FMISO and FDG signals respectively. The procedure for carrying 
out compartmental analysis of FMISO and FDG dynamic PET with both radiotracers imaged 
within the same PET imaging session is shown in diagram 3. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-186 A(7) 
Approval date: 22-Dec-2023 
Page 17 of 36 
 
 
 
 
• TLC: Thin Layer Tomography 
• IF: Input Function 
• TAC: Time Activity Curve 
• CA: Compartmental Analysis 
• KRC: Kinetic Rate Constant 
• Sim: Radiotherapy Simulation 
Diagram 3. 
 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
There will be no specific monitoring after the studies. All patients will be evaluated according to 
the standard of care for their lung cancer. Their imaging studies performed as part of standard of 
care every 3-4 months and their vital status will be periodically monitored for 3 years following 
treatment for the progression free survival and overall survival analyses. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-186 A(7) 
Approval date: 22-Dec-2023 
Page 18 of 36 
 
 
 
Day 0 
18F- 
Mid Treatment Scans 
Follow up 
BH 18F-FDG 
FMISO1 
18F-FMISO2 
18F-FDG 
PET/CT 
(within 14 +/- 
5 days after the 
baseline 18F- 
FDG scan, and 
before starting 
therapy) 
Within occur two 
weeks +/- 4 days post 
initiation of therapy 
(FDG: 3 to 4 weeks 
+/- 4 days post- 
initiation of therapy 
Informed consent 
X 
Review of your history 
and medication 
X 
Physical exam 
X 
Vital signs 
X 
X 
Standard clinical 18F- 
FDG PET/CT scan 
X 
X 
18F-FMISO tracer 
injection 
X1 
X1 
X 
Research PET scans 
X 
X 
X 
X 
Research blood draws 
X 
X 
Review of medical 
record for PFS and OS 
X 
Standard clinical CT of 
the chest 
X3 
Vital signs and Toxicity 
assessment2 
X 
X 
Table 1. Group 1: FMISO 2 Mid-Treatment Group Study Outline 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-186 A(7) 
Approval date: 22-Dec-2023 
Page 19 of 36 
 
 
 
Day 0 
18F-FDG 
PET/CT 
18F- 
FMISO1 
(within 14 +/- 
5 days after the 
baseline 18F- 
FDG scan, and 
before starting 
therapy) 
Simultaneous 
18F- 
FDG/18FMISO 
2 
(at least one day after 
the first 18F-FMISO 
scan but before 
starting therapy. This 
must also be within 
14 +/- 5 days after 
baseline FDG scan) 
Optional Mid 
Treatment 
18F-FDG 
(3 weeks +/- 4 days 
after RT) 
Follow up 
Informed consent 
X 
Review of your history 
and medication 
X 
Physical exam 
X 
Vital signs 
X 
X 
Standard clinical 18F- 
FDG PET/CT scan 
X 
X 
18F-FMISO tracer 
injection 
X1,2 
X1,2 
X 
Research PET scans 
X 
X 
X 
X 
Research blood draws 
X 
X 
X 
Review of medical 
record for PFS and OS 
X 
Standard clinical CT of 
the chest 
X3 
Vital signs and Toxicity 
assessment2 
X 
Table 2. Group 2: Simultaneous FDG and FMISO group study outline 
 
1. The 18F-FMISO and the simultaneous 18F-FDG/18F-FMISO studies on each day will be 
performed in up to three separate imaging sessions, as was described earlier. 
2. Vital signs and toxicity assessments will be performed immediately after each FMISO scan 
session. Additionally, approximately 24 hours (or on the next business day) after the 
completion of each scan session, a toxicity assessment will be completed via a telephone 
followup. 
3. CT of the chest will be performed every 3 to 4 months from the completion of treatment for 3 
years as per standard clinical care. 
 
11.0 
TOXICITIES/SIDE EFFECTS 
No acute side effects are expected as a result of this study. However, in the unlikely event that an 
adverse reaction to either radiopharmaceutical occurs, the results must be documented and reported 
by the Principal Investigator to both the Institutional Review Board, and the Investigative New Drug 
Committee. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-186 A(7) 
Approval date: 22-Dec-2023 
Page 20 of 36 
 
 
To ensure patient safety, vital signs and toxicity assessments will be performed immediately after 
each scan session. Additionally, approximately 24 hours (or on the next business day) after the 
completion of each scan session, a toxicity assessment will be completed via a telephone followup. 
 
The risks of this study include exposure to unnecessary radiation. This risk will be clearly outlined in 
the informed consent. 
Adverse Events will be graded using the NCI Common Terminology Criteria for ADverse Events- 
Version 4.0. 
Information about both diagnostic agents, 18F-FDG and FMISO, and the corresponding dosimetry 
tables are summarized below. 
 
 
11.1 
18F-FDG PET Scan 
11.1.1 18F-FDG PET Schedule 
 
18F-FDG is an FDA approved radiotracer. In patients who are receiving radiation and agree to 
participate in this protocol, one additional 18F-FDG PET scan will be obtained mid-treatment 
(as described in section 1.0) to assess response to therapy. This follow up FDG scan is 
investigational. Besides, in the baseline FDG PET/CT, which is standard of care, additional two 
one PET/CT FOV over the lesion will be acquired following the clinical scan. This additional 
FOV is investigational and will be acquired first in FB and then in BH (same as for the 
investigational follow up FDG PET/CT study). The CT components will be acquired in cine 
mode and then BH respectively. 
 
Only patients in Group 1 will participate in BH scans. 
 
11.1.2 18F-FDG Production 
 
All 18F-FDG doses will be purchased from IBA. 
 
11.1.3 Dosimetry Estimates for 18F-FDG 
 
Table 3 below summarizes normal organ doses due to 18F- FDG administration. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-186 A(7) 
Approval date: 22-Dec-2023 
Page 21 of 36 
 
 
 
 
Absorbed Doses 
Follow Up FDG PET/CT 
 
 
Target Organ 
Median Dose (rad/mCi) 
0.903 rad(*) + Dose (rad) 
per 12mCi FDG 
0.903 rad(*) + 0.837 rad(**) 
Dose (rad) per 12mCi FDG 
 
 
Adrenals 
0.052 
0.624 
0.624 
Bone Surfaces 
0.037 
0.444 
0.444 
Brain 
0.17 
2.04 
2.04 
Gall Bladder Wall 
0.088 
1.056 
1.056 
Heart Wall 
0.25 
3.903 
4.74 
Kidneys 
0.078 
0.936 
0.936 
Large Intestine - Lower Wall 
0.059 
0.708 
0.708 
Large Intestine - Upeer Wall 
0.048 
0.576 
0.576 
Lens of Eye 
0.041 
0.492 
0.492 
Liver 
0.088 
1.056 
1.056 
Lungs 
0.0028 
0.9366 
1.7736 
Muscle / Other Tissue 
0.041 
0.492 
0.492 
Pancreas 
0.052 
0.624 
0.624 
Red Marrow 
0.041 
1.395 
2.232 
Small Intestine 
0.048 
0.576 
0.576 
Stomach Wall 
0.044 
0.528 
0.528 
Testes 
0.056 
0.672 
0.672 
Thyroid 
0.012 
0.144 
0.144 
Total Body 
0.043 
0.516 
0.516 
Urinary Bladdr Wall 
45 min Voiding Interval 
0.165 
1.98 
1.98 
1 hr Voiding Interval 
0.22 
2.64 
2.64 
1.5 hrs Voiding Interval 
0.34 
4.08 
4.08 
2 hr Voiding Interval 
0.44 
5.28 
5.28 
Effective Dose Equivalent (rem) 
0.1 
1.46187 
1.7046 
 
(*) Cumulative CT dose from FB-CT (0.066 rad), BH-CT (0.066 rad), and 4D-CT (0.771 rad) (Total = 0.903 rad) 
(**) Cumulative CT dose from BH-CT (0.066 rad) and 4D-CT (0.771 rad) (Total = 0.837 rad) 
 
(1) FDG Package Insert, Eastern Isotopes, Inc, Asbnun, VA, 1998. 
(2) Wu et al. Eur J Nucl Mol Imaging 31:38-43, 2004. 
 
Table 3. 
 
The organ receiving highest radiation dose from the investigational 18F-FDG scan is the heart 
wall ( 3.0 rad ). Additional doses of 0.066 rad from the FB CT, 0.771 rad from one 4D-CT scans 
(avg CT) and 0.066 rad from a BH-CT will be delivered to the patient. The total dose to the 
heart wall from the investigational 18F-FDG scan is 4.74 rad. 
 
11.2 
18F-FMISO PET Scan 
11.2.1 18F-FMISO PET Schedule 
18F-FMISO is a radiotracer which MSKCC holds an approved IND. In patients who agree to 
participate in this protocol, two 18F-FMISO PET Scans will be obtained within 5 days, at least 
1 day after the baseline 18F-FDG-PET that is required as part of pretreatment enrollment criteria. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-186 A(7) 
Approval date: 22-Dec-2023 
Page 22 of 36 
 
 
 
 
11.2.2 18F-FMISO Production 
F18-fluoride is produced by the Memorial Sloan-Kettering Cancer Center cyclotron by proton 
irradiation of an enriched O-18 water target in a small-volume titanium chamber. 18F- FMISO 
is prepared at an approximate specific activity of 2.5x107MBq/mmol at production 
time. Patients will be injected with a maximum of 10 +/- 10% mCi of 18F-FMISO on each of 
the 2 18F-FMISO scan days. 
11.2.3 Dosimetry Estimates for 18F-FMISO 
Bio-distribution data has been obtained for 25patients at the University of Washington, and 
dosimetry was performed. Table 4 below summarizes normal organ doses due to 18F- FMISO 
administration. 
 
 
 
F18-FMISO Patient Dosimetry 
Absorbed Doses 
Target Organ 
Median Dose (rad/mCi) 
2.51 rad(*) + Dose (rad) per 
10mCi FMISO 
2x2.51 rad(*) + Dose (rad) per 2x10mCi FMISO 
Adrenals 
0.0614 
0.614 
1.228 
Brain 
0.0318 
0.318 
0.636 
Breasts 
0.0455 
0.455 
0.91 
Heart Wall 
0.0685 
3.195 
6.39 
Stomach 
0.0466 
0.466 
0.932 
Kidney 
0.0581 
0.581 
1.162 
Liver 
0.0677 
0.677 
1.354 
Lungs 
0.0366 
2.876 
5.752 
Muscle 
0.0525 
0.525 
1.05 
Ovaries 
0.0651 
0.651 
1.302 
Red Marrow 
0.0403 
2.913 
5.826 
Spleen 
0.0603 
0.603 
1.206 
Thyroid 
0.0559 
0.559 
1.118 
Eye Lens 
0.057 
0.57 
1.14 
Total Body 
0.0466 
0.466 
0.932 
Urinary Bladder Wall 
45 min Voiding Interval 
0.0291 
0.291 
0.582 
1 hr Voiding Interval 
0.0389 
0.389 
0.778 
1.5 hrs Voiding Interval 
0.0583 
0.583 
1.166 
2 hr Voiding Interval 
0.0777 
0.777 
1.554 
Uterus 
0.0677 
0.677 
1.354 
Effective Dose Equivalent (rem) 
0.0481 
0.481 
0.962 
 
Table 4. 
 
The organ receiving highest radiation dose from the two 18F-FMISO scans is the heart wall ( 
2x0.685 rad). Additional doses from 6 BH-CT scans (3 BH-CT per 18F-FMISO study) of 0.396 
rad (6 x 0.066 rad) , and six 4D-CT scans (avg CT) (three 4D-CT per 18F-FMISO study) of 
4.626 rad (6 x 0.771 rad) for a total of 2.51 rad per 18F-FMISO study or 5.02 rad for both 18F- 


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IRB Number: 13-186 A(7) 
Approval date: 22-Dec-2023 
Page 23 of 36 
 
 
FMISO studies, will be delivered to the patient bringing the total radiation dose to the heart 
wall to 6.39 rad . 
11.2.4 Dosimetry Estimates for simultaneous 18F-FMISO/18F-FDG 
Based on the dosimetry data of tables 1 and 2, dosimetry was performed. Table 5 below 
summarizes normal organ doses due to simultaneous 18F-FMISO/18F-FDG administration. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-186 A(7) 
Approval date: 22-Dec-2023 
Page 24 of 36 
 
 
 
Absorbed Doses 
Dual FDG/FMISO 
Dose (rad) per 
0.198rad + 2.313 rad + 
Dose (rad) per 8mCi 
Target Organ 
Dose (rad) per 8mCi FDG 
8mCi FMISO 
FMISO + per 8mCi FDG 
Adrenals 
0.416 
0.491 
0.907 
Bone Surfaces 
0.296 
0.228 
0.524 
Brain 
1.36 
0.254 
1.614 
Gall Bladder Wall 
0.704 
0.438 
1.142 
Heart Wall 
2 
0.548 
5.059 
Kidneys 
0.624 
0.465 
1.089 
Large Intestine - Lower Wall 
0.472 
0.423 
0.895 
Large Intestine - Upeer Wall 
0.384 
0.414 
0.798 
Lens of Eye 
0.328 
0.456 
0.784 
Liver 
0.704 
0.542 
1.246 
Lungs 
0.0224 
0.293 
2.826 
Muscle / Other Tissue 
0.328 
0.420 
0.748 
Pancreas 
0.416 
0.530 
0.946 
Red Marrow 
0.328 
0.322 
3.161 
Small Intestine 
0.384 
0.390 
0.774 
Stomach Wall 
0.352 
0.373 
0.725 
Testes 
0.448 
0.432 
0.880 
Thyroid 
0.096 
0.447 
0.543 
Total Body 
Urinary Bladdr Wall 
0.344 
0.373 
0.717 
45 min Voiding Interval 
1.32 
0.233 
1.553 
1 hr Voiding Interval 
1.76 
0.311 
2.071 
1.5 hrs Voiding Interval 
2.72 
0.466 
3.186 
2 hr Voiding Interval 
3.52 
0.622 
4.142 
Effective Dose Equivalent (rem) 
0.8 
0.385 
1.185 
 
(1) FDG Package Insert, Eastern Isotopes, Inc, Asbnun, VA, 1998. 
(2) Wu et al. Eur J Nucl Mol Imaging 31:38-43, 2004. 
 
Table 5. 
The organ receiving highest radiation dose from the combined FMISO/FDG scan is the heart wall ( 
2.548 rad). Additional doses from 3 BH-CT scans (3 BH-CT per 18F-FMISO study) of 0.198 rad (3 x 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-186 A(7) 
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Page 25 of 36 
 
 
0.066 rad) , and three 4D-CT scans (avg CT) (three 4D-CT per 18F-FMISO study) of 2.313 rad (3 x 
0.771 rad), bringing the total dose to the heart to 5.059 rad per FMISO/FDG study. 
 
11.2.5 Total Doses from All Studies 
Based on the dosimetry data of tables 1 and 2, dosimetry was performed. Table 6 below summarizes 
the total normal organ doses from the FDG PET/CT, 2xFMISO PET/CT, and combined FMISO/FDG 
PET/CT. 
 
 
Absorbed Doses 
 
Total Dose from All FDG and FMISO studies (including the corresponding CT-BH's amd 4DCT's) 
Target Organ 
0.903 rad(*) + 0.837 
 
0.198rad + 2.313 rad + Dose 
2x2.51 rad(*) + Dose (rad) per 
rad(**) Dose (rad) per 
(rad) per 8mCi FMISO + per 
Total Dose 
12mCi FDG 
2x10mCi FMISO 
8mCi FDG 
Adrenals 
0.624 
1.228 
0.907 
2.759 
Bone Surfaces 
0.444 
0.57 
0.524 
1.538 
Brain 
2.04 
0.636 
1.614 
4.290 
Gall Bladder Wall 
1.056 
1.095 
1.142 
3.293 
Heart Wall 
4.74 
6.39 
5.059 
16.189 
Kidneys 
0.936 
1.162 
1.089 
3.187 
Large Intestine - Lower Wall 
0.708 
1.0575 
0.895 
2.661 
Large Intestine - Upeer Wall 
0.576 
1.035 
0.798 
2.409 
Lens of Eye 
0.492 
1.14 
0.784 
2.416 
Liver 
1.056 
1.354 
1.246 
3.656 
Lungs 
1.7736 
5.752 
2.826 
10.352 
Muscle / Other Tissue 
0.492 
1.05 
0.748 
2.290 
Pancreas 
0.624 
1.325 
0.946 
2.895 
Red Marrow 
2.232 
5.826 
3.161 
11.219 
Small Intestine 
0.576 
0.975 
0.774 
2.325 
Stomach Wall 
0.528 
0.932 
0.725 
2.185 
Testes 
0.672 
1.08 
0.880 
2.632 
Thyroid 
0.144 
1.118 
0.543 
1.805 
Total Body 
Urinary Bladdr Wall 
0.516 
0.932 
0.717 
2.165 
45 min Voiding Interval 
1.98 
0.582 
1.553 
4.115 
1 hr Voiding Interval 
2.64 
0.778 
2.071 
5.489 
1.5 hrs Voiding Interval 
4.08 
1.166 
3.186 
8.432 
2 hr Voiding Interval 
5.28 
1.554 
4.142 
10.976 
Effective Dose Equivalent (rem) 
1.2 
0.962 
1.185 
3.347 
 
(1) FDG Package Insert, Eastern Isotopes, Inc, Asbnun, VA, 1998. 
(2) Wu et al. Eur J Nucl Mol Imaging 31:38-43, 2004. 
Table 6. 
The organ receiving the highest radiation dose in the case of the five patients that will undergo the 
combined FMISO/FDG study is the heart at 16.189 rad. This is based on the doses from the mid- 
treatment FDG scan, the baseline and follow up FMISO scan, the combined FMISO/FDG scan, and all 
the corresponding CT’s. 


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IRB Number: 13-186 A(7) 
Approval date: 22-Dec-2023 
Page 26 of 36 
 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
There are two primary goals for this study; first, to assess the reproducibility of kinetic analysis of 
dynamic 18F-FMISO PET images, in both BH and FB data sets, and second, to assess the prognostic 
value of hypoxia, as measured with 18F-FMISO PET, with OS and PFS in NSCLC. As explained 
above, the presence and extent of tumor hypoxia will be measured by means of kinetic analysis of 
dynamic 18F-FMISO PET images. Kinetic analysis parameters may be susceptible to breathing- 
induced motion artifacts due to patient respiration. Hence, the correlation of outcome to both the 
presence and extent of tumor hypoxia may be inaccurate .We will therefore conduct analyses based 
on BH- and FB- PET datasets, and then compare the results in order to assess the effect breathing on 
these parameters. This exploratory objective of tumor hypoxia correlation to clinical endpoints is 
dependent on time to tumor progression and death. We will follow up with these patients up to a 
maximum of three years. The table below summarizes the milestones of this research project. 
Likewise, the predictive value of FDG PET may also be suspect due to breathing motion artifacts. In 
light of the discussion above, therefore, the secondary aim is to compare the predictive value of FDG 
PET when the data are acquired in BH versus in FB PET. 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
If at any time the patient develops unacceptable toxicity he/she will be removed from study. An 
unacceptable toxicity will be defined by a grade III/IV toxicity requiring hospitalization as per 
CTCAE v4.0 
 
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 (i.e., a change in diagnosis), the patient will be removed from 
the study. 
 
Patients who are withdrawn from the study before completing all protocol required scans will be 
replaced to ensure there are 25 evaluable patients. 
 
 
14.0 
BIOSTATISTICS 
This study will enroll 25 patients with non-small cell lung cancer (NSCLC) who will undergo treatment 
with definitive conventionally fractionated radiation therapy (RT), neoadjuvant chemotherapy, or chemo-RT. 
In addition to standard of care PET/CT scans, they will also be scanned twice at baseline (pre-treatment) with 
experimental 18F-FMISO scans. 
 
Since some patients will have multiple lesions some of the statistical analyses will be lesion-based and 
some will be patient-based. This is explained in detail within each analysis but primarily, 
reproducibility analyses will be lesion-based and analysis of predictive values will be patient-based. 
Presence and extent of hypoxia will be analyzed twice, one lesion-based and the other patient-based. 
One of the primary objectives is to evaluate the reproducibility of kinetic analysis in serial, BH and 
Free-Breathing (FB), dynamic 18F-FMISO PET images. Hypoxia is measured by k3, the trapping rate 
(see section 7.3). This will be analyzed both as a binary and a continuous variable: if any of the voxels 


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IRB Number: 13-186 A(7) 
Approval date: 22-Dec-2023 
Page 27 of 36 
 
 
inside the tumor has a k3>0.1 the tumor is defined to be hypoxic while its extent will be defined by the 
fraction of hypoxic volume which is the fraction of tumor volume with k3>0.1. Reproducibility will be 
evaluated using Cohen’s kappa for presence of hypoxia and concordance correlation coefficient for the 
extent of hypoxia. This will be a lesion-based analysis and multiple observations per patient will be 
taken into account using a variance inflation factor estimated from the intraclass correlation coefficient. 
 
Another primary objective is to compare the presence and extent of hypoxia with the clinical outcome 
(see section 7.3 and above for the definition of hypoxia). Previous studies showed comparable 
outcomes for stage IIIA (which is the majority treated) when following either of the two treatment arms 
considered in this study (51, 52). 
 
Therefore, data from both groups of patients will be analyzed together. Historical data suggests 38% 
of patients will be free of recurrence at 3 years (53), which provides us with approximately 80% power 
to detect a hazard ratio of 3.0 between groups of low and high change. This calculation is based on a 
log-rank test and assumes that extent of hypoxia is dichotomized at observed median resulting in equal 
group sizes and maximal power. This is for planning purposes only. We will use Cox regression with 
extent of hypoxia as the covariate in two different ways: (1) lesion-based analysis with an estimating 
equations to account for multiple observations per patient; (2) patient-based where an aggregate 
measure of extent of hypoxia (sum of the fraction of tumor volumes with k3>0.1 across all lesions) 
over all lesions within a patient) will be used as a covariate. In addition, a lesion and patient-based 
analyses for presence of hypoxia will also be considered where, for the patient-based analysis, the 
aggregate measure will be defined as presence of hypoxia in at least one of the lesions. 
In an exploratory analysis to address the secondary objective of assessing the predictive value of FDG 
PET/CT in a group of twenty five lung cancer patients undergoing radiotherapy or concurrent 
chemoradiotherapy, we will use the concordance probability estimate from a proportional hazars 
regression model with SUV as the predictor for the outcomes of survival and progression-free survival. 
Time of origin will be the start time of therapy (neoadjuvant therapy, if applicable, concurrent 
chemoradiation or radiation alone otherwise). We will use these estimates to preliminarily determine 
whether BH PET/CT provides greater predictive capability than Free-Breathing (FB) PET/CT. Since 
these analyses are exploratory findings will be interpreted as hypothesis-generating. 
 
We expect to accrue one patient a month for each of the two cohorts. 
 
 
15.0 
RESEARCH PARTICIPANT 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. 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 


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IRB Number: 13-186 A(7) 
Approval date: 22-Dec-2023 
Page 28 of 36 
 
 
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. Registrations must be submitted via the PPR Electronic 
Registration System (http://ppr/). The completed signature page of the written consent/RA or 
verbal script/RA, a completed Eligibility Checklist and other relevant documents must be 
uploaded via the PPR Electronic Registration System. 
15.2 
Randomization 
 
 
16.0 
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. Study personnel will record 
clinical data in each patient’s source documents (i.e., the patient’s medical record). The 
investigator will maintain adequate and accurate records to enable the conduct of the study to 
be fully documented and the study data to be subsequently verified. After study closure, the 
investigator will maintain all source documents, study-related documents, and the data stored 
in the database used for data collection. Data will be entered throughout the duration of the 
trial as patients are enrolled 
16.1 
Quality Assurance 
Eligibility of patients will be verified with the principal investigator. Only the designated 
investigators can obtain informed consent. 
 
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 QA) 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 committees: 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 Institutional Review Board (see section 
16.2). 
During the protocol development and review process, each protocol will be assessed for the 
level of risk and the degree of required monitoring. Every type of protocol (e.g., NIH 
sponsored, in-house sponsored, industrial sponsored, NCI cooperative group, etc.) is reviewed 
and monitoring procedures are established at the time of protocol activation. 


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IRB Number: 13-186 A(7) 
Approval date: 22-Dec-2023 
Page 29 of 36 
 
 
16.2 
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://cancertrials.nci.nih.gov/researchers/dsm/index.html. 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://mskweb2.mskcc.org/irb/index.htm. 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
There are no foreseen additional risks to the patients from this study. 
 
Risks of Study Participation: Patients in this study will be receiving current standard of care 
for their specific disease site. 
 
Financial Costs to Patients: All diagnostic and therapeutic interventions except for the 
FMISO-PET scans and the mid-treatment FDG PET/CT are part of the current routine care of 
patients/subjects eligible for this study and. A research grant will cover the cost of the 
FMISO-PET scans and the tracer, blood PK samplings and the mid-treatment FDG PET/CT. 
There are no additional financial costs or burden to the patient beyond the charges routinely 
incurred as part of standard medical care. 
 
Patient Confidentiality: Patient/subject privacy and confidentiality will be maintained 
according to MSKCC guidelines and all data derived from this study will be kept in a secure 
database. All data and results will be anonymously reported with regard to individual 
subjects. 
 
Voluntary nature of the study: Subjects will be made aware of the voluntary nature of the 
study as part of the informed consent process. They will be allowed to withdraw participation 
at any time without the risk of alteration in the quality of their medical care. 
 
 
 
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 


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IRB Number: 13-186 A(7) 
Approval date: 22-Dec-2023 
Page 30 of 36 
 
 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board. 
 
17.2 
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 subject 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 signs consent. SAE reporting is required for 30- 
days after the participant’s last investigational treatment or intervention. Any events that occur after 
the 30-day period and that are at least possibly related to protocol treatment must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 ‘Reporting of Serious Adverse 
Events’, the SAE report must be sent to the IRB within 5 calendar days of the event. The IRB requires 
a Clinical Research Database (CRDB) SAE report be submitted electronically to the SAE Office as 
follows: 
For IND/IDE trials: Reports that include a Grade 5 SAE should be sent to saegrade5@mskcc.org. All 
other reports should be sent to saemskind@mskcc.org. 
 
For all other trials: Reports that include a Grade 5 SAE should be sent to saegrade5@mskcc.org. All 
other reports should be sent to sae@mskcc.org. 
The report should contain the following information: 
Fields populated from CRDB: 
• 
Subject’s initials 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 


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IRB Number: 13-186 A(7) 
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Page 31 of 36 
 
 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject 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 
The PI’s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB SAE report should be completed as per above instructions. If appropriate, the report will be 
forwarded to the FDA by the SAE staff through the IND Office. 
 
 
17.2.1 
Any additional SAE reporting information required by the sponsor or drug supplier should be included 
in this section. 
 
 
18.0 
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. 


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IRB Number: 13-186 A(7) 
Approval date: 22-Dec-2023 
Page 32 of 36 
 
 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
19.0 
REFERENCES 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-186 A(7) 
Approval date: 22-Dec-2023 
Page 33 of 36 
 
 
1. 
Ryu JS, Choi NC, Fischman AJ, Lynch TJ, and Mathisen DJ, FDG-PET in staging and 
restaging non-small cell lung cancer after neoadjuvant chemoradiotherapy: correlation with 
histopathology. Lung Cancer, 2002. 35(2): p. 179-87. 
2. 
Farrell MA, McAdams HP, Herndon JE, and Patz EF, Jr., Non-small cell lung cancer: FDG 
PET for nodal staging in patients with stage I disease. Radiology, 2000. 215(3): p. 886-90. 
3. 
Liu BJ, Dong JC, Xu CQ, et al., Accuracy of 18F-FDG PET/CT for lymph node staging in 
non-small-cell lung cancers. Chin Med J (Engl), 2009. 122(15): p. 1749-54. 
4. 
Bradley J, Thorstad WL, Mutic S, et al., Impact of FDG-PET on radiation therapy volume 
delineation in non-small-cell lung cancer. Int J Radiat Oncol Biol Phys, 2004. 59(1): p. 78- 
86. 
5. 
de Geus-Oei LF, van der Heijden HF, Corstens FH, and Oyen WJ, Predictive and prognostic 
value of FDG-PET in nonsmall-cell lung cancer: a systematic review. Cancer, 2007. 110(8): 
p. 1654-64. 
6. 
Vansteenkiste JF, Stroobants SG, De Leyn PR, Dupont PJ, Verbeken EK, and Leuven Lung 
CGrp, Potential use of FDG-PET scan after induction chemotherapy in surgically staged IIIa- 
N-2 non-small-cell lung cancer: A prospective pilot study. Annals of Oncology, 1998. 9(11): 
p. 1193-1198. 
7. 
Hoekstra CJ, Stroobants SG, Smit EF, et al., Prognostic relevance of response evaluation 
using [F-18]-2-fluoro-2-deoxy-D-glucose positron emission tomography in patients with 
locally advanced non-small-cell lung cancer. Journal of Clinical Oncology, 2005. 23(33): p. 
8362-8370. 
8. 
Choi NC, Fischman AJ, Niemierko A, et al., Dose-response relationship between probability 
of pathologic tumor control and glucose metabolic rate measured with FDG pet after 
preoperative chemoradiotherapy in locally advanced non-small-cell lung cancer. 
International Journal of Radiation Oncology Biology Physics, 2002. 54(4): p. 1024-1035. 
9. 
Mac Manus MP, Hicks RJ, Matthews JP, Wirth A, Rischin D, and Ball DL, Metabolic (FDG- 
PET) response after radical radiotherapy/chemoradiotherapy for non-small cell lung cancer 
correlates with patterns of failure. Lung Cancer, 2005. 49(1): p. 95-108. 
10. 
Cerfolio RJ, Bryant AS, Winokur TS, Ohja B, and Bartolucci AA, Repeat FDG-PET after 
neoadjuvant therapy is a predictor of pathologic response in patients with non-small cell lung 
cancer. Annals of Thoracic Surgery, 2004. 78(6): p. 1903-1909. 
11. 
Kong FM, Frey KA, Quint LE, et al., A pilot study of [18F]fluorodeoxyglucose positron 
emission tomography scans during and after radiation-based therapy in patients with non 
small-cell lung cancer. J Clin Oncol, 2007. 25(21): p. 3116-23. 
12. 
Ding XP, Zhang J, Li BS, et al., Feasibility of Shrinking Field Radiation Therapy through 
18F-FDG PET/CT after 40 Gy for Stage III Non-Small Cell Lung Cancers. Asian Pacific 
Journal of Cancer Prevention, 2012. 13(1): p. 319-323. 
13. 
Madani I, Duprez F, Boterberg T, et al., Maximum tolerated dose in a phase I trial on 
adaptive dose painting by numbers for head and neck cancer. Radiotherapy and Oncology, 
2011. 101(3): p. 351-355. 
14. 
Duprez F, De Neve W, De Gersem W, Coghe M, and Madani I, Adaptive Dose Painting by 
Numbers for Head-and-Neck Cancer. International Journal of Radiation Oncology Biology 
Physics, 2011. 80(4): p. 1045-1055. 
15. 
Madani I, Duprez F, De Gersem W, Coghe M, and De Neve W, Phase I Trial on Adaptive 
Dose Painting by Numbers for Head and Neck Cancer: What is the Maximum Tolerated 
Dose? International Journal of Radiation Oncology Biology Physics, 2010. 78(3): p. S82-S82. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-186 A(7) 
Approval date: 22-Dec-2023 
Page 34 of 36 
 
 
16. 
Hockel M, Schlenger K, Aral B, Mitze M, Schaffer U, and Vaupel P, Association between 
tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer 
Res, 1996. 56(19): p. 4509-15. 
17. 
Hockel M and Vaupel P, Biological consequences of tumor hypoxia. Semin Oncol, 2001. 28(2 
Suppl 8): p. 36-41. 
18. 
Okunieff P, Ding I, Vaupel P, and Hockel M, Evidence for and against hypoxia as the 
primary cause of tumor aggressiveness. Adv Exp Med Biol, 2003. 510: p. 69-75. 
19. 
Parker C, Milosevic M, Toi A, et al., Polarographic electrode study of tumor oxygenation in 
clinically localized prostate cancer. Int J Radiat Oncol Biol Phys, 2004. 58(3): p. 750-7. 
20. 
Vaupel P, Briest S, and Hockel M, Hypoxia in breast cancer: pathogenesis, characterization 
and biological/therapeutic implications. Wien Med Wochenschr, 2002. 152(13-14): p. 334- 
42. 
21. 
Vaupel P, Hockel M, and Mayer A, Detection and characterization of tumor hypoxia using 
pO2 histography. Antioxid Redox Signal, 2007. 9(8): p. 1221-35. 
22. 
Vaupel P, Mayer A, and Hockel M, Tumor hypoxia and malignant progression. Methods 
Enzymol, 2004. 381: p. 335-54. 
23. 
Nordsmark M, Eriksen JG, Gebski V, Alsner J, Horsman MR, and Overgaard J, Differential 
risk assessments from five hypoxia specific assays: The basis for biologically adapted 
individualized radiotherapy in advanced head and neck cancer patients. Radiother Oncol, 
2007. 83(3): p. 389-97. 
24. 
Nordsmark M, Loncaster J, Aquino-Parsons C, et al., Measurements of hypoxia using 
pimonidazole and polarographic oxygen-sensitive electrodes in human cervix carcinomas. 
Radiother Oncol, 2003. 67(1): p. 35-44. 
25. 
Rademakers SE, Lok J, van der Kogel AJ, Bussink J, and Kaanders JH, Metabolic markers in 
relation to hypoxia; staining patterns and colocalization of pimonidazole, HIF-1alpha, CAIX, 
LDH-5, GLUT-1, MCT1 and MCT4. BMC Cancer, 2011. 11: p. 167. 
26. 
Graves EE, Vilalta M, Cecic IK, et al., Hypoxia in Models of Lung Cancer: Implications for 
Targeted Therapeutics. Clinical Cancer Research, 2010. 16(19): p. 4843-4852. 
27. 
Machtay M, Paulus R, Moughan J, et al., Defining Local-Regional Control and Its 
Importance in Locally Advanced Non-small Cell Lung Carcinoma A Radiation Therapy 
Oncology Group Analysis. Journal of Thoracic Oncology, 2012. 7(4): p. 716-722. 
28. 
Rosenzweig KE, Fox JL, Yorke E, et al., Results of a phase I dose-escalation study using 
three-dimensional conformal radiotherapy in the treatment of inoperable nonsmall cell lung 
carcinoma. Cancer, 2005. 103(10): p. 2118-2127. 
29. 
Bradley JD, Moughan J, Graham MV, et al., A phase I/II radiation dose escalation study with 
concurrent chemotherapy for patients with inoperable stages I to III non-small-cell lung 
cancer: phase I results of RTOG 0117. Int J Radiat Oncol Biol Phys, 2010. 77(2): p. 367-72. 
30. 
Machtay M, Bae K, Movsas B, et al., Higher Biologically Effective Dose of Radiotherapy Is 
Associated with Improved Outcomes for Locally Advanced Non-Small Cell Lung Carcinoma 
Treated with Chemoradiation: An Analysis of the Radiation Therapy Oncology Group. 
International Journal of Radiation Oncology Biology Physics, 2012. 82(1): p. 425-434. 
31. 
Jeffrey D Bradley RP, Ritsuko Komaki, Gregory A. Masters, Kenneth Forster, Steven E. 
Schild, Jeffrey Bogart, Yolanda I. Garces, Samir Narayan, Vivek Kavadi, Lucien Alexander 
Nedzi, Jeff M. Michalski, Douglas Johnson, Robert Malcolm MacRae, Walter John Curran, 
Hak Choy, , A randomized phase III comparison of standard-dose (60 Gy) versus high-dose 
(74 Gy) conformal chemoradiotherapy with or without cetuximab for stage III non-small cell 
lung cancer: Results on radiation dose in RTOG 0617. J Clin Oncol, 2013. suppl; abstr 
7501(31). 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-186 A(7) 
Approval date: 22-Dec-2023 
Page 35 of 36 
 
 
32. 
Eschmann SM, Paulsen F, Reimold M, et al., Prognostic impact of hypoxia imaging with 
18F-misonidazole PET in non-small cell lung cancer and head and neck cancer before 
radiotherapy. J Nucl Med, 2005. 46(2): p. 253-60. 
33. 
Rasey JS, Koh WJ, Evans ML, et al., Quantifying regional hypoxia in human tumors with 
positron emission tomography of [18F]fluoromisonidazole: a pretherapy study of 37 patients. 
Int J Radiat Oncol Biol Phys, 1996. 36(2): p. 417-28. 
34. 
Sun JD, Liu Q, Wang J, et al., Selective tumor hypoxia targeting by hypoxia-activated 
prodrug TH-302 inhibits tumor growth in preclinical models of cancer. Clin Cancer Res, 
2012. 18(3): p. 758-70. 
35. 
Meng F, Evans JW, Bhupathi D, et al., Molecular and cellular pharmacology of the hypoxia- 
activated prodrug TH-302. Mol Cancer Ther, 2012. 11(3): p. 740-51. 
36. 
Horsman MR, Nordsmark M, Khalil AA, et al., Reducing acute and chronic hypoxia in 
tumours by combining nicotinamide with carbogen breathing. Acta Oncol, 1994. 33(4): p. 
371-6. 
37. 
Gagel B, Reinartz P, Demirel C, et al., [18F] fluoromisonidazole and [18F] 
fluorodeoxyglucose positron emission tomography in response evaluation after chemo- 
/radiotherapy of non-small-cell lung cancer: a feasibility study. BMC Cancer, 2006. 6: p. 51. 
38. 
Eschmann SM, Paulsen F, Reimold M, et al., Prognostic impact of hypoxia imaging with F- 
18-misonidazole PET in non-small cell lung cancer and head and neck cancer before 
radiotherapy. Journal of Nuclear Medicine, 2005. 46(2): p. 253-260. 
39. 
Casciari JJ, Graham MM, and Rasey JS, A modeling approach for quantifying tumor hypoxia 
with [F-18]fluoromisonidazole PET time-activity data. Med Phys, 1995. 22(7): p. 1127-39. 
40. 
Thorwarth D, Eschmann SM, Paulsen F, and Alber M, A kinetic model for dynamic [18F]- 
Fmiso PET data to analyse tumour hypoxia. Phys Med Biol, 2005. 50(10): p. 2209-24. 
41. 
Wang W, Lee NY, Georgi JC, et al., Pharmacokinetic analysis of hypoxia (18)F- 
fluoromisonidazole dynamic PET in head and neck cancer. J Nucl Med, 2010. 51(1): p. 37- 
45. 
42. 
Nehmeh SA, Erdi YE, Meirelles GS, et al., Deep-inspiration breath-hold PET/CT of the 
thorax. J Nucl Med, 2007. 48(1): p. 22-6. 
43. 
Lee N, Nehmeh S, Schoder H, et al., Prospective trial incorporating pre-/mid-treatment 
[18F]-misonidazole positron emission tomography for head-and-neck cancer patients 
undergoing concurrent chemoradiotherapy. Int J Radiat Oncol Biol Phys, 2009. 75(1): p. 
101-8. 
44. 
Andreyev A and Celler A, Dual-isotope PET using positron-gamma emitters. Physics in 
Medicine and Biology, 2011. 56(14): p. 4539-4556. 
45. 
Rietzel E, Pan T, and Chen GT, Four-dimensional computed tomography: image formation 
and clinical protocol. Med Phys, 2005. 32(4): p. 874-89. 
46. 
Nehmeh SA, Erdi YE, Ling CC, et al., Effect of respiratory gating on quantifying PET images 
of lung cancer. J Nucl Med, 2002. 43(7): p. 876-81. 
47. 
Nehmeh SA, Erdi YE, Rosenzweig KE, et al., Reduction of respiratory motion artifacts in 
PET imaging of lung cancer by respiratory correlated dynamic PET: methodology and 
comparison with respiratory gated PET. J Nucl Med, 2003. 44(10): p. 1644-8. 
48. 
Nehmeh SA, Erdi YE, Ling CC, et al., Effect of respiratory gating on reducing lung motion 
artifacts in PET imaging of lung cancer. Med Phys, 2002. 29(3): p. 366-71. 
49. 
Sarikaya I, Yeung HW, Erdi Y, and Larson SM, Respiratory artefact causing malpositioning 
of liver dome lesion in right lower lung. Clin Nucl Med, 2003. 28(11): p. 943-4. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 13-186 A(7) 
Approval date: 22-Dec-2023 
Page 36 of 36 
 
 
50. 
Meirelles GSP, Erdi YE, Nehmeh SA, et al., Deep-inspiration breath-hold PET/CT: Clinical 
findings with a new technique for detection and characterization of thoracic lesions. Journal 
of Nuclear Medicine, 2007. 48(5): p. 712-719. 
51. 
Albain KS, Swann RS, Rusch VW, et al., Radiotherapy plus chemotherapy with or without 
surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled 
trial. Lancet, 2009. 374(9687): p. 379-386. 
52. 
van Meerbeeck JP, Kramer GW, Van Schil PE, et al., Randomized controlled trial of 
resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell 
lung cancer. J Natl Cancer Inst, 2007. 99(6): p. 442-50. 
53. 
Auperin A, Le Pechoux C, Rolland E, et al., Meta-Analysis of Concomitant Versus Sequential 
Radiochemotherapy in Locally Advanced Non-Small-Cell Lung Cancer. Journal of Clinical 
Oncology, 2010. 28(13): p. 2181-2190. 
20.0 
APPENDICES 
Not applicable.