A Feasibility Study Using Fluorine-18-Labeled Fluoro-Misonidazole Positron Emission Tomography to Detect Hypoxia in Locally Advanced (T3-T4 and./or N1)Primary Rectal Cancer Patients
Phase: NA
Conditions: Colorectal Cancer
Sponsor: Memorial Sloan Kettering Cancer Center

Memorial Sloan Kettering Cancer Center 
IRB Number: 07-151 A(10) 
Approval date: 06-Apr-2020 
 
A Feasibility Study Using Fluorine-18-Labeled Fluoro-Misonidazole Positron Emission 
Tomography to Detect Hypoxia in Colorectal Cancer Patients 
 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
Principal Investigator/Department: 
John Humm, M.D. 
Medical Physics/ Imaging/ 
Spectroscopic Physics 
Co-Principal 
Investigator(s)/Department: 
Heiko Schöder, M.D. 
Nuclear Medicine 
Investigator(s)/Department: 
Zhigang Zhang, Ph.D. 
Joe O’Donoghue, Ph.D. 
Pat Zanzonico, Ph.D. 
Steven Larson, M.D. 
Nancy Y. Lee, M.D. 
Julio Garcia-Aguilar, M.D. 
Philip B. Paty, M.D. 
Martin R. Weiser, M.D. 
Garrett Nash, M.D. 
Epidemiology & Biostatistics 
Medical Physics 
Medical Physics 
Nuclear Medicine 
Radiation Oncology 
Surgery 
Surgery 
Surgery 
Surgery 
Consenting 
Professional(s)/Department: 
Heiko Schöder, M.D. 
Julio Garcia-Aguilar, M.D. 
Philip B. Paty, M.D. 
Martin R. Weiser, M.D. 
Garrett Nash, M.D. 
Iris Wei, M.D. 
John Humm, M.D. 
Nuclear Medicine 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Medical Physics/ Imaging/ 
Spectroscopic Physics 
 
Please note: All listed above must have complete the mandatory Human Subjects 
Education and Certification and Good Clinical Practice Certification Programs. 
 
Participating Institutions – If multicenter 
study coordinated by MSK: 
PI's Name 
Site's Role 
University of North Carolina at Chapel Hill 
Jose Guillem, M.D., MPH 
Data or Specimen Analysis 
Only 

Memorial Sloan Kettering Cancer Center 
IRB Number: 07-151 A(10) 
Approval date: 06-Apr-2020 
 
Table of Contents 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL .............. ERROR! BOOKMARK NOT 
DEFINED. 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ................................................................. 1 
2.0 
OBJECTIVE AND SCIENTIFIC AIMS ............................................................................. 1 
3.0 
BACKGROUND AND RATIONALE ................................................................................ 2 
3.1 
HYPOXIA ................................................................................................................ 2 
3.2 
18F-FMISO PET ....................................................................................................... 3 
3.3 
PET STUDIES.......................................................................................................... 4 
3.4 
TRIALS .................................................................................................................... 5 
3.5 
SUMMARY ............................................................................................................. 6 
4.0 
OVERVIEW OF STUDY DESIGN AND INTERVENTION ............................................ 6 
4.1 
DESIGN ................................................................................................................... 6 
4.2 
INTERVENTION .................................................................................................... 7 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ........................................................................ 9 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ...................................................................... 11 
6.1 
SUBJECT INCLUSION CRITERIA ..................................................................... 11 
6.2 
SUBJECT EXCLUSION CRITERIA .................................................................... 11 
7.0 
RECRUITMENT PLAN .................................................................................................... 11 
8.0 
PRETREATMENT EVALUATION ................................................................................. 12 
9.0 
TREATMENT/INTERVENTION PLAN ......................................................................... 12 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION .......................................... 13 
11.0 
TOXICITIES/SIDE EFFECTS .......................................................................................... 13 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ................ 14 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ................................................................. 14 
14.0 
BIOSTATISTICS ............................................................................................................... 14 
15.0 
SUBJECT REGISTRATION AND RANDOMIZATION PROCEDURES ..................... 16 
15.1 
SUBJECT REGISTRATION ................................................................................. 16 
16.0 
DATA MANAGEMENT ISSUES ..................................................................................... 16 
16.1 
QUALITY ASSURANCE ..................................................................................... 16 
16.2 
DATA AND SAFETY MONITORING ................................................................ 17 
17.0 
PROTECTION OF HUMAN SUBJECTS ......................................................................... 17 
17.1 
PRIVACY .............................................................................................................. 18 
17.2 
SERIOUS ADVERSE EVENT (SAE) REPORTING ........................................... 18 
18.0 
INFORMED CONSENT PROCEDURES ......................................................................... 20 
18.1 
RESEARCH AUTHORIZATION ..... ERROR! BOOKMARK NOT DEFINED. 
19.0 
REFERENCES ................................................................................................................... 20 

Memorial Sloan Kettering Cancer Center 
IRB Number: 07-151 A(10) 
Approval date: 06-Apr-2020 
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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
This is a 2-stage feasibility study of the non-invasive detection of tumor hypoxia 
using fluorine-18-labeled fluoro-misonidazole (18F-FMISO), a PET tracer of 
hypoxia. The primary objective is to determine the feasibility of a non-invasive 
method of detecting hypoxia, 18F-FMISO-PET imaging, in colorectal cancer 
patients, with feasibility defined as the ability to identify regions of interest (ROI) 
on the 18F-FMISO scan that distinguish hypoxic versus normoxic regions in 
colorectal tumors. 
Please note that all patients entered on this protocol will undergo the standard of 
care for their disease site. The information obtained from the use of 18F-FMISO 
PET scans will NOT be used to guide patients’ treatment on this protocol. 
 
This study is being performed under the FDA’s Radioactive Drug Research 
Committee (RDRC) program. 
Schema: 
1.1 
Evaluation and consent. 
 
1.2 
A CT scout and attenuation scan will be performed on a 
combination PET/CT scanner to identify and localize the tumor at 
the center of the 15 cm PET scanner field of view. The patient 
will be injected while in the scan position with the 18F-FMISO 
hypoxia-specific radiotracer. Simultaneous with the injection, a 
dynamic PET will be initiated, to collect radiotracer 
pharmacokinetic information. 
1.3 
The dynamic PET image frames will be used to analyze the 
hypoxia-specific radiotracer uptake and assist in determining the 
distribution of tumor hypoxia. 
1.4 
Digital autoradiography will be performed on the resected 
specimen in patients who undergo surgery on the same day as the 
18F-FMISO PET. 
 
2.0 
OBJECTIVE AND SCIENTIFIC AIMS 
Our primary objective is to determine the feasibility of a non-invasive method of 
detecting hypoxia, using 18F-FMISO-PET imaging in colorectal cancer patients. 
Feasibility is defined as the ability to identify regions of interest (ROI) on the 18F- 
FMISO-PET images that distinguish between hypoxic and normoxic regions within 
colorectal tumors. 
Secondary objectives include determining the volume of hypoxic tumor ROIs as a 
proportion of the entire tumor volume by this non-invasive imaging technique. ROIs 
are defined as those voxels, within the tumor volume defined on FDG PET/CT, for 
which the 18F-FMISO radioactivity concentratio n is greater than 1.2 times that 

Memorial Sloan Kettering Cancer Center 
IRB Number: 07-151 A(10) 
Approval date: 06-Apr-2020 
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measured in blood. Selection of this threshold is based on the largest body of 18F- 
FMISO studies in humans (20, 21). 
 
We will also obtain pharmacokinetic data on the biodistribution of 18F-FMISO in 
patients with colorectal cancer to determine the optimal interval between drug 
administration and PET imaging. 
Digital autoradiography, when performed, will allow us to determine the 
correspondence between the micro-distribution of 18F-FMISO and the tumor 
histology. 
 
3.0 
BACKGROUND AND RATIONALE 
3.1 
Hypoxia 
Hypoxia is a characteristic feature of malignant solid tumors that has been well 
established (1,2). Unlike healthy tissues, many tumors contain a fraction of 
hypoxic cells, which immunohistochemical studies suggest consist of areas of up 
to several hundred microns in diameter that are poorly perfused (3). It is well 
known that hypoxia renders tumor cells up to three times more resistant to 
ionizing radiation than aerobic cells (1-3). In addition to increased 
radioresistance, hypoxia is associated with a more aggressive phenotype and 
increased metastatic potential (4,5). It has also been shown in several studies to 
be an important determinant of loco-regional control of head and neck tumors 
(6,7). 
A large amount of direct and indirect evidence also supports the presence of a 
significant hypoxic fraction in human rectal cancer. Hemoglobin saturation of red 
blood cells within microvessels averaged 43% in rectal cancer biopsies vs. 80% in 
the corresponding biopsies of normal rectal mucosa (8). Direct in vivo pO2 
measurement with polarographic electrodes in human rectal cancer have revealed 
a mean pO2 of 20-30 mm Hg (8-11), with 23-45% of all measured values below 
10 mm Hg (10,11). Also noted in these studies is the marked heterogeneity of 
oxygenation in rectal tumors. This heterogeneity may explain the wide extent of 
rectal cancer response to preoperative combined modality therapy (12). 
 
 
There is mounting evidence that hypoxia is not only a potentially important 
prognostic factor in patients with rectal cancer, but in colon cancer patients as 
well. Studies utilizing immunohistochemical techniques have identified certain 
proteins, up-regulated during hypoxic conditions, correlate with increased rates of 
lymph node and distant metastasis (30), tumor recurrence and overall survival 
(31,32). This data suggests that hypoxic tumors may behave more aggressively 
than normoxic tumors. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 07-151 A(10) 
Approval date: 06-Apr-2020 
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As hypoxia is a known cause of radioresistance (1-3)(particularly important with 
regard to tumors that are treated with radiation therapy, such as locally advanced 
or recurrent rectal cancers and head & neck cancers), a number of methods aimed 
at improving tumor oxygenation are currently under investigation (ie. hyperbaric 
oxygen therapy (33), carbogen breathing (34) or administration of vasoactive 
agents (35)). Currently, the most extensively studied method includes 
administration of radiosensitizing agents (eg. Tirapazamine) concurrently with 
radiotherapy (36). 
 
Tirapazamine, a hypoxic cytotoxin, preferentially targets hypoxic cells and 
induces DNA double strand breaks, leading to cell death. As demonstrated in 
head and neck cancer, cancer of the uterine cervix and non small cell lung cancer, 
tirapazamine holds promise as both a radiosensitizer and has synergistic 
chemotherapeutic effect when combined with cisplatin. This drug has been 
studied here at MSKCC in patients with cervical and non-small cell lung cancer 
(IRB Protocols 94-082, 94-114, 96-062), and is currently under investigation as 
an adjunct in patients undergoing chemoradiotherapy for cervical cancer (IRB 
Protocol 07-128). 
 
If we are able to demonstrate that colon cancers contain a significant hypoxic 
fraction, we can justify the study of tirapazamine (or similar compounds) in 
patients with colorectal cancer. Currently, oxaliplatin is both highly active and 
widely used in the treatment of colon cancer patients. If active these patients, 
tirapazamine, in conjunction with oxaliplatin, may prove more efficacious than 
current chemotherapeutic regimens. 
PET is a noninvasive imaging modality with the potential to identify tumor 
hypoxia through the use of hypoxia-targeting radiotracers. If these hypoxic 
regions are identified, they (a) may translate into a new prognostic indicator of 
therapeutic outcome and (b) be specifically targeted with additional radiation and 
perhaps translate into further improvement in local control. 
3.2 
18F-FMISO PET 
18F-FMISO PET is a recently developed imaging modality useful in detecting and 
quantifying hypoxic regions within tumors. This tool has been studied both in 
vitro and in vivo across a wide range of human tumor types. While it is well 
established that polarographic needle electrode assessment of tissue oxygen 
tension is considered the “gold standard” for detecting and measuring degree of 
hypoxia, we continue to investigate new, less invasive techniques. A number of 
studies comparing 18F-FMISO PET imaging to needle electrode measurements in 
advanced head and neck tumors and soft tissue sarcomas have validated its use in 
studying hypoxia (13, 29) 
Radiolabeled nitroimidazoles (including 18F-FMISO) have emerged as useful non- 
invasive markers of hypoxia. These molecules, in their native form, are lipophilic 
and freely diffusible across cell membranes. Once intracellular, they undergo an 

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enzymatic reduction reaction. In the presence of oxygen, this reaction is rapidly 
reversed and the molecule is free to diffuse out of the cell, obtaining 
transmembrane equilibrium. In a hypoxic environment, the reduced molecule 
covalently binds to intracellular macromolecules, effectively trapping it within the 
cell (20, 28). 
 
 
At our institution, in a rat prostate cancer tumor model, as well as in two 
colorectal cancer xenograft models, 18F-FMISO microPET imaging has been used 
to detect tumor hypoxia. These results were corroborated by measuring pO2 
directly using the OxyLite probe system (14). Preliminary results support the 
feasibility of imaging hypoxic subvolumes in some tumors, and we propose its 
use in studying colorectal tumors. 
 
3.3 
PET Studies 
PET studies using hypoxic markers have also been performed in patients both at 
other centers as well as at MSKCC. For example, Rasey, et al. has demonstrated 
the efficacy of PET imaging with 18F-FMISO in quantifying hypoxia in both head 
and neck and lung cancer patients (13). Hypoxia was observed in 97% of the 
tumors studied with 18F-FMISO PET imaging, and median fractional hypoxic 
volumes of 48% for lung cancer and 9% for head and neck cancer were detected. 
The extent of hypoxia varied markedly between tumors of the same site or of the 
same histology. Hypoxia was also distributed non-uniformly between regions 
within a given tumor. 
Eschmann, et al. suggests that the efficacy of radiotherapy can be predicted on the 
basis of the kinetic behavior of 18F-FMISO in tumors of head and neck and non- 
small cell lung cancer (15). Dr. Nancy Lee, in the Dept. of Radiation Oncology at 
MSKCC, has successfully completed a study of 20 head and neck cancer patients 
using 18F-FMISO PET, in which 18/20 showed 18F-FMISO tumor uptake (16). In 

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this protocol, we propose to investigate 18F-FMISO PET imaging in patients with 
colorectal cancer. 
 
3.4 
Trials 
A phase I trial of concurrent tirapazamine, a hypoxic cell sensitizer, cisplatin, and 
radiotherapy in the treatment of advanced head and neck cancer has been 
completed at the Peter MacCallum Cancer Institute in Australia (17). All patients 
underwent 18F-FMISO PET to demonstrate tumor hypoxia. All patients also had 
baseline FDG PET scans and the 18F-FMISO and FDG scans were co-registered. 
18F-FMISO PET scans in this study were obtained two hours after radiotracer 
administration. All PET imaging was performed on a dedicated PET scanner with 
the data processed using measured attenuation correction and iterative 
reconstruction. Fourteen out of the fifteen patients had detectable hypoxia on 
baseline 18F-FMISO scan with focal abnormality corresponding to a region of 
increased FDG uptake in either the primary lesion or the nodal mass. In all cases, 
the intensity of 18F-FMISO uptake was less than the corresponding FDG 
abnormality. On the co-registered PET images, necrotic regions, as evidenced by 
central photopenia on FDG PET, demonstrated 18F-FMISO distribution only at 
the inner border of FDG uptake. In those regions without necrosis on FDG PET, 
only the central part of the metabolically active lesion had 18F-FMISO retention. 
The pattern of 18F-FMISO uptake was consistent with the expected pattern of 
hypoxia in tumor tissue being adjacent to areas of tumor necrosis or in the center 
of non-necrotic lesions. The rapid normalization (i.e. reduction in tumor uptake) 
of 18F-FMISO PET scans suggests successful treatment of the hypoxic 
component. 
In another phase I trial, also done at the Peter MacCallum Cancer Institute in 
Australia (18), patients with inoperable rectal cancer or symptomatic primary 
rectal cancer with metastasis were given oxaliplatin on day 1 of weeks 1, 3 and 5 
of radiotherapy. Dose level 1 was oxaliplatin 70 mg m-2 with 5-FU 200 mg m-2 
day-1 continuous infusion 96 h week-1. On dose level 2, the oxaliplatin dose was 
increased to 85 mg m-2. On dose level 3, the duration of the 5-FU was increased 
to 168 h week-1. Pelvic radiotherapy was 45 Gray (Gy) in 25 fractions over 5 
weeks with a boost of 5.4 Gy. FDG- and 18F-FMISO-PET were used to assess 
metabolic tumor response and hypoxia. In total, 16 patients were accrued. Dose- 
limiting toxicities occurred in one patient at level 2 (grade 3 chest infection), and 
two patients at level 3 (grade 3 diarrhea). Dose level 2 was declared the 
recommended dose level. FDG-PET imaging showed metabolic responses in 11 
of the 12 primary tumors assessed. Four of six tumors had detectable hypoxia on 
18F-FMISO scans. 
A prospective study from Germany (22) on 103 patients with locally advanced 
cancer of the uterine cervix demonstrated that tumor oxygenation, measured with 
a standardized polarographic method, is a strong pre-therapeutic prognostic 
factor. Patients with hypoxic tumors had a significantly worse disease-free and 

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overall survival following surgery alone, mainly due to locoregional failures with 
or without distant metastases. 
 
3.5 
Summary 
Hypoxia is a characteristic feature of malignant solid tumors associated with poor 
prognosis and resistance to chemotherapy and radiation. It has also been shown 
(6) that the presence of hypoxia may reduce long-term survival post surgery. 
Hypoxia renders tumor cells up to three times more resistant to ionizing radiation 
than aerobic cells. The presence of hypoxic regions within tumors may be one 
factor leading to local failure after treatment with standard pre-operative 
radiotherapy doses. If these regions could be identified and verified using a non- 
invasive imaging technique prior to surgery, they could be specifically targeted 
using sophisticated planning techniques such as intensity modulated radiation 
therapy (IMRT) to deliver higher doses ionizing radiation with pre-operative 
radiotherapy. Future studies using IMRT to “dose paint” areas of hypoxia within 
tumors will build upon the results of this feasibility study. Ultimately, by the 
delivery of differential dose of radiation to the tumor, in combination with 
surgery, the local control rates of rectal cancer patients may further be improved. 
 
4.0 
OVERVIEW OF STUDY DESIGN AND INTERVENTION 
4.1 
Design 
All patients will undergo the standard of care for their colorectal cancer and will 
have an FDG PET/CT scan performed within six weeks of a dynamic 18F-FMISO 
PET/CT scan. We will accept FDG PET scans not performed at MSKCC if the 
outside study was performed as a dedicated PET/CT and the full data set 
(including all CT and PET images) is submitted digitally to us accompanied by a 
report clearly indicating the administered activity, uptake time and blood glucose 
level at the time of the study. The patient will receive no treatment between the 
two scans. Both scans will be performed before radiochemotherapy. The FDG 
PET scan will be used to delineate the tumor volume. The accompanying CT of 
both FDG and 18F-FMISO will be co-registered, to allow selection of the 18F- 
FMISO intra-tumoral hypoxic voxels. 
 
Regions of interest (ROI) corresponding to hypoxic tumor sub-volumes will be 
defined as those voxels, within the tumor volume defined on FDG PET/CT, for 
which the 18F-FMISO radioactivity concentration is greater than 1.2 times that 
measured in blood. The selection of this threshold is in concordance with the 
largest body of 18F-FMISO studies in man (20, 21), which were successfully 
adopted in our own studies in head and neck cancers by Dr. Nancy Lee. 
This is a feasibility trial using a 2-stage design. In the first stage, 15 patients will 
receive an 18F-FMISO PET scan. If 4 or fewer patients have ROIs, the study will 
be stopped but if 5 or more patients have ROIs then an additional 15 patients at 
most will be scanned. We will therefore scan a maximum of 30 patients in order 

Memorial Sloan Kettering Cancer Center 
IRB Number: 07-151 A(10) 
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to determine the hypoxia fraction in colorectal cancer using 18F-FMISO. We 
anticipate the need to enroll approximately 50 patients to account for withdrawals 
of consent or inability of subjects to complete protocol requirement in order to 
achieve our target of 30 completed scans. Once this has been established, we 
propose a larger trial in order to correlate hypoxia fraction with treatment 
outcome. 
 
Digital autoradiography will be performed on frozen tumor tissue sections 
obtained from the resected specimen in patients who undergo surgery on the same 
day as the 18F-FMISO PET in order to determine the micro-distribution of 18F- 
FMISO (see details in Section 4.2, “Intervention”). 
 
 
4.2 
Intervention 
18F-FMISO PET scan 
Dynamic PET scans will be performed on one of the GE Discovery PET/CT 
scanners in 2D mode. The patient will be set up in the radiotherapy treatment 
position with intra-venous lines for radiotracer injection and for venous blood 
sampling. A CT scan 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. 
Immediately thereafter, a single 370 MBq (10 mCi) dose of 18F-MISO will be 
injected as a bolus, and the dynamic scan initiated coincident with the injection. 
Data will be acquired in 1-minute time intervals continuously from 0-30 minutes. 
The patient will then be removed from the scanner. Since no further 18F-FMISO 
will be injected in the patient, there will be no further radiation exposure from 
radiopharmaceutical. The 2nd PET scan (optional and performed at 90 minutes) 
and the 3rd PET scan (non-optional and performed between 120-240 minutes) will 
each consist of a 10-minute image of the tumor consisting of two consecutive 5- 
minute time frames. A 15-cm body segment low dose CT scan will be performed 
at each of these two additional image sessions for attenuation correction and 
image registration. The radiation dose of the first CT scan will be 0.9 mCi and 
the dose for the 2nd (optional) and 3rd (non-optional) scans will be 0.1 mCi each, 
for a total exposure of 1.0-1.1 mCi for all 3 CT scans. This total dose is 
approximately equivalent to one half (1/2) of the radiation exposure from a single 
diagnostic CT scan. To further improve patient image registration, the patient 
will have markers placed on the skin, inferior and superior to the lesion, to 
facilitate accurate laser set-up for the subsequent 2nd (optional) and 3rd (non- 
optional) scans. 

Memorial Sloan Kettering Cancer Center 
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Note that the patient will receive the radiation dose from only one 18F-FMISO 
injection and from 2-3 low-dose CT scans. For a detailed estimate of radiation 
absorbed doses to organs as a result of these scans, please refer to Table 1. 
 
 
 
Blood pharmacokinetic sampling 
 
For pharmacokinetic modeling, the dynamic data of the 18F-MISO radiotracer in 
the tumor must be supplemented by clearance data from the blood. This data will 
be ascertained by ROI analysis on an artery defined on the PET images. A limited 
number of blood samples (up to a maximum of 3) will be drawn (if possible) for 
the purpose of calibrating the image ROI data. When blood samples are taken, 
they shall be acquired at pre-designated times in conjunction with the PET scan 
from a single I.V. line inserted into the patient prior to the procedure. One blood 
sample will be taken per imaging time point, for a total of 2-3 blood samples. 
Between 1 and 3 cc of blood will be removed at each time point (making the 
maximum volume of blood withdrawn during this study < 9 cc). 
 
These samples will be weighed and counted on a sensitive well scintillation 
counter in the nuclear medicine clinic by skilled nuclear medicine laboratory 
personnel for the purpose of an accurate determination of the amount of 
radioactive tracer in the blood versus time. The blood sample data will allow 
tumor-to-blood ratios to be determined for each of the imaging time points and 
provide information on the evolution of radiotracer entrapment within the hypoxic 
tumor regions. The kinetics of tumor uptake and blood clearance will be used to 
determine the optimal time to perform the 18F-FMISO scan. Once 
pharmacokinetic modeling is complete, blood sampling will be discontinued. 
Therefore, not all 30 patients who undergo 18F-FMISO scans will necessarily have 
blood sampling during imaging. 
 
Digital Autoradiography 
Digital autoradiography will be performed on the resected specimen for those 
patients who undergo surgery on the same day as the 18F-FMISO scan,. Two 
tissue samples will be analyzed. The samples will be cubes with approximate 
dimensions of 5mm x 5mm x 5mm. The first sample will be taken from an 18F- 
FMISO-avid (“hot”) section of the resected tumor, and the second sample will be 
taken from an 18F-FMISO-negative (“cold”) section of the resected tumor. In 
instances when the entire tumor is “cold” and the surgical specimen contains 
adequate tissue, the first sample will consist of representative tumor tissue and the 
second sample will consist of adjacent normal mucosa. 
Tissue samples will be individually wrapped in heavy-duty Saran Wrap film and 
immersed into pre-chilled methylbutane (Fisher Scientific, Pittsburgh, PA) at 

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-80˚C for 10 minutes. The frozen tissue samples will then be embedded in 
Optimal Cutting Temperature (OCT) compound (VWR Scientific, Rochester, 
NY) on dry ice and transferred to a -80˚C freezer for 30 minutes. Sets of 
contiguous frozen 8µm-thick sections will be cut from each tissue sample using a 
Microm HM500 cryostat microtome (Microm, Waldorf, Germany) and collected 
on glass microscope slides. A minimum of three frozen tissue sections from each 
specimen will be placed in a film cassette against a Fujifilm BAS-MS2325 
imaging plate (Fuji Photo Film Co, Tokyo, Japan). Latent images will be read out 
after a 24-48 hr exposure time using a Fujifilm BAS-1800II Bio-Imaging 
Analyzer (Fuji Photo Film Co) at 50µm pixel resolution. Digital autoradiography 
image intensity will be characterized by the machine readout parameter of 
photostimulable luminescence per square mm (PSL/mm2). Tracer uptake will be 
derived from region-of-interest analysis of the digital autoradiography images 
using dedicated software. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
F-18 FDG is the only commercially available radiopharmaceutical approved by 
the FDA for the intended use in study patients/subjects. 
F-18 labeled FMISO is prepared and tested for quality assurance in this study 
within the Cyclotron/Radiochemistry Core Facility at MSKCC. The 
radiopharmaceutical is being utilized in this protocol with authorization of the 
MSKCC Radioactive Drug Research Committee (RDRC). 18F-FMISO is prepared 
at an approximate specific activity of 1-2 Ci/mole at end of bombardment time. 
For PET imaging of tumor uptake, 370 MBq (10.0 mCi) in 1-3 ml sterile saline 
will be administered IV. The maximum mass of fluoromisonidazole that will be 
administered is 1 microgram. The no observable effect level (NOEL) is at mass 
dose >1 milligram. 
 
Radionuclide dosimetry 
 
Biodistribution data on FMISO has been obtained for 60 patients at the University 
of Washington School of Medicine, and dosimetry was performed. Estimates of 
normal organ absorbed doses following FMISO administration were published by 
Graham et al. (22) and are summarized in the table on the following page. 
 
Table 1 
Radiation Absorbed Doses to Organs following 18F-MISO administration and 
CT Scans 
 
Target Organ 
Median Dose 
(mGy/MBq) 
Dose (cGy) 
per 370 MBq 
(10mCi) injection 
Total Dose (cGy) 
per 370 MBq (10mCi) 
injection + CT Scans 
Adrenals 
0.0166 
1.71 
0.61 

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Brain 
0.0086 
0.32 
0.32 
Breasts 
0.0123 
0.46 
0.46 
Gall bladder wall 
0.0148 
1.65 
0.55 
Lower Large Intestine 
0.0143 
0.53 
1.63 
Small Intestine 
0.0132 
0.49 
2.69 
Stomach 
0.0126 
0.47 
0.47 
Upper Large Intestine 
0.0140 
0.52 
0.52 
Heart Wall 
0.0185 
0.68 
0.68 
Kidney 
0.0157 
0.58 
1.68 
Liver 
0.0183 
0.68 
1.78 
Lungs 
0.0099 
0.37 
0.37 
Muscle 
0.0142 
0.53 
0.53 
Ovaries 
0.0176 
0.65 
1.75 
Pancreas 
0.0179 
0.66 
1.76 
Red Marrow 
0.0109 
0.40 
0.40 
Bone Surface 
0.0077 
0.28 
0.28 
Skin 
0.0048 
0.18 
1.28 
Spleen 
0.0163 
0.60 
1.70 
Testes 
0.0146 
0.54 
0.54 
Thymus 
0.0155 
0.57 
0.57 
Thyroid 
0.0151 
0.56 
0.56 
Urinary Bladder Wall 
0.0210 
0.78 
1.88 
Uterus 
0.0183 
0.68 
1.78 
Eye Lens 
0.0154 
0.57 
0.57 
Total Body 
0.0126 
0.47 
0.47 
 
This study will entail a single injection of 370 MBq (10 mCi) of 18F-MISO per 
patient. Absorbed dose estimates, derived from the University of Washington 
data, indicate that the urinary bladder wall is anticipated to experience the largest 
dose of any normal organ. The absorbed dose to the urinary bladder wall is 
estimated as 0.78 cGy (7.8 mSv) for the 18F-FMISO administration. Patients will 
receive additional radiation dose due to the CT component of the study. This 
contribution is estimated to be 1.1 cGy (1 mSv) for the three PET-CT scans and 
will be applicable only to the exposed pelvic region of the patient. The dose to 
the eye from the 18F-MISO administration is estimated to be 0.57 cGy (5.7 mSv). 
No additional eye dose will be delivered by CT scanning. The total body radiation 
dose from 18F-MISO is estimated to be 0.47 cGy (4.7 mSv). These estimates are 
well below the values of 3 cGy and 5 cGy permitted by the FDA to radiation 
sensitive or normal organs respectively, for an experimental radiopharmaceutical. 
The total radiation dose for this investigation is thus within the prescribed 
guidelines set for RDRC approval. Additionally, this study will not significantly 
add to the total radiation dose experienced by the patient as a consequence of their 
treatment for rectal cancer. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 07-151 A(10) 
Approval date: 06-Apr-2020 
-11- 
 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
6.1 
Subject Inclusion Criteria 
• Able to provide written informed consent 
 
• Histologically confirmed diagnosis of colorectal adenocarcinoma 
 
• 18 years of age or older 
 
• Karnofsky performance status ≥ 70 
 
6.2 
Subject Exclusion Criteria 
 
 
 
• Women who are pregnant (confirmed by serum b-HCG in women of 
reproductive age) or breast feeding 
 
7.0 
RECRUITMENT PLAN 
All patients meeting the eligibility requirements will be considered for enrollme nt 
regardless of sex, race, or religion. A member of the colorectal research team will 
screen the clinics of the investigators named on the protocol to identify potentially 
eligible patients. These patients will be made aware of the protocol, its specific 
aims and objectives, and the potential risks and benefits the patient may incur. 
Patients will be required to read, agree to, and sign an IRB-approved informed 
consent form prior to registration on this trial. Patients will be consented by their 
treating physician. 
 
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/re search 
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 
Because they will be asked to come in to the hospital for an additional day, patients 
will be given a $100 honorarium to cover gas, tolls, parking, meals and any 
incidental expenses associated with this additional day. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 07-151 A(10) 
Approval date: 06-Apr-2020 
-12- 
 
 
 
8.0 
PRETREATMENT EVALUATION 
All patients will undergo standard of care tests including an FDG PET scan. 
 
9.0 
TREATMENT/INTERVENTION PLAN 
Within six weeks of the FDG PET scan, patients will undergo an 18F-FMISO PET 
scan. Patients will receive no treatment between the two scans. The 18F-FMISO 
scan will be conducted as follows: 
 
• An I.V. line will be placed in each of the left and right forearms (i.e., a 
total of 2 I.V. lines). One line will be used exclusively for radiotracer 
injection and the other exclusively for blood sampling (see below). 
 
 
• A scout view, followed by a low-dose CT of the tumor region will be 
obtained. 
 
• The couch will automatically advance into the PET detector component of 
the scanner so that the tumor is in the center of the 15 cm PET field of 
view. 
 
• The patient will be injected intravenously with 370 MBq (10 mCi) of 18F- 
FMISO, simultaneously with the start of PET image acquisition. 
 
• Dynamic images consisting of five 1-minute images and five 5-minutes 
images (duration 30-minutes) will be acquired within one 15 cm field of 
view. 
• Patient will be taken out of the scanner. 
 
• Patient will undergo a 2nd (optional) PET scan at 90 minutes and a 3rd 
(non-optional) PET scan at 120-240 minutes post-injection. These scans 
will consist of a 10-minute PET acquisition and a low-dose CT. 
 
• When blood sampling is required, up to a maximum of 3 blood samples 
will be obtained using the second I.V. line immediately at selected times 
post-injection and during the PET scan procedure. Samples will be taken 
with each imaging time point. Between 1 and 3 cc of blood will be 
removed at each time point (making the maximum volume of blood 
withdrawn during this study < 9 cc). 
• . 

Memorial Sloan Kettering Cancer Center 
IRB Number: 07-151 A(10) 
Approval date: 06-Apr-2020 
-13- 
 
 
o These samples will be weighed and counted in the Nuclear 
Medicine laboratory for the purpose of determining the blood 
clearance kinetics and the tumor input function. 
 
• At the end of the entire study, the I.V. lines will be removed. 
 
• The radiopharmacy will keep a log of all injected activity. All patient 
doses are permanently recorded in the Nuclear Pharmacy database. The 
injected 18F-FMISO dose, injection time and scan time are also recorded in 
the PET image file header, and can be accessed from the PET images 
themselves. 
 
• Digital autoradiography will be performed on up to two tissue samples 
from patients who undergo surgery on the same day as the 18F-FMISO 
scan (see details in Section 4.2, “Intervention”). 
 
• The RSA assigned to the study will be responsible for identifying eligible 
patients from the colorectal service clinics. The RSA will work closely 
with the POAs and RSAs in the Department of Radiology to coordinate 
scheduling of patients’ research procedures and will track patients who are 
on study to ensure they follow the treatment schedule outlined above. 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
There are no follow-up requirements for this study. All patients will undergo 
standard of care for their colorectal cancer and will be evaluated accordingly. 
 
11.0 
TOXICITIES/SIDE EFFECTS 
The safety of various radiopharmaceuticals has been reviewed. In a 5-year 
prospective study (1989 to 1994) of 18 institutions in the United States, the 
prevalence of adverse events following radiopharmaceutical administration was 
0.0023% (23). The adverse experiences reported included rash, chest discomfort, 
light headedness, nausea, mild anaphylaxis, diaphoresis, vomiting and headache. 
In a prospective study of 22 PET centers from 1994 to 1997, there were no 
adverse events reported during 81,801 administered doses of PET 
pharmaceuticals (24). In a similar study of 17 nuclear medicine departments in 
Europe in 1996, the prevalence of adverse events was 11 events per 100,000 
radiopharmaceutical administrations (25). There were no serious or life- 
threatening events, and no deaths reported in the literature. 
 
A similar study to that proposed has been carried out at MSKCC featuring 
FMISO PET scanning in Head and Neck cancer patients (IRB # 04-070). No side 
effects, including allergic reactions and claustrophobia, have been noted (16). 
Study patients will also be exposed to radiation during the study, both from the 
CT component of the PET CT and from the 18F-MISO itself. At the dose levels 

Memorial Sloan Kettering Cancer Center 
IRB Number: 07-151 A(10) 
Approval date: 06-Apr-2020 
-14- 
 
 
outlined in section 5.0, there have been no reported radiation-related side effects 
in the literature. 
 
In the unlikely event of an adverse reaction, this will be documented and reported 
by the Principal Investigator to the Institutional SAE Manager (307 East 63rd 
Street, 1st Floor) as well as to the RDRC. 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
This is a pilot study which aims to obtain pharmacokinetic data on the 
biodistribution of FMISO in patients with colorectal cancer. It will also assess the 
feasibility of detecting hypoxia by non-invasive 18F-FMISO PET imaging in 
colorectal carcinoma patients, and to do this will utilize a dynamic PET 
acquisition sequence that will provide kinetic tumor uptake data, which when 
combined with blood clearance kinetics through compartmental modeling may 
provide useful parametric maps of the variation of intra-tumor hypoxia. Whereas, 
in this study, we will not obtain direct gold-standard measurements of tumor 
hypoxia using a pO2 microelectrode, we and others have confirmed by 
autoradiography that the 18F-FMISO tracer distribution accurately correlates with 
both exogenous (pimonidazole) and endogenous (HIF-1α and carboanhydrase 9) 
immunohisto-chemical markers of hypoxia. 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
If at any time the patient withdraws consent he/she will be removed from the 
study. 
 
If at any time the patient develops unacceptable toxicity he/she will be removed 
from the study. Although we have never had any adverse effects from the FMISO 
administration and none have been reported elsewhere (see section 11.0), allergic 
reaction is always a possibility and any patient experiencing this would be sent 
immediately to the Urgent Care unit for treatment, reported to the Principal 
Investigator, and removed from the study. 
 
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. 
Please note that all patients whether included in this study or not will receive the 
standard of care radiation treatments. 
 
14.0 
BIOSTATISTICS 
This is a feasibility study of using 18F-FMISO PET to detect tumor hypoxia in 
colorectal cancer. Prospective patients will be scanned using 18F-FMISO PET to 
identify the hypoxic regions. Analysis of the PET data will be conducted by one 

Memorial Sloan Kettering Cancer Center 
IRB Number: 07-151 A(10) 
Approval date: 06-Apr-2020 
-15- 
 
 
of the physicists in Nuclear Medicine, who will use a software package designed 
to analyze on a voxel by voxel basis the kinetics of FMISO uptake and clearance 
in the tumors. 
The primary objective of the study is to determine the feasibility of the imaging 
with 18F-FMISO in colorectal cancer patients. Feasibility is defined as identifying 
regions of interest (ROI) in the 18F-FMISO PET scan. In an earlier protocol with 
FMISO in head and neck cancer, 18 of 20 patients had identifiable ROIs. Since 
published data (26, 27) reveal that upwards of 40% of all, non selected early and 
advanced rectal cancers are considered to be hypoxic, and since the patients we 
will be studying in this protocol have large bulky, locally advanced rectal cancers, 
we anticipate that perhaps as many as 70% of our rectal cancers will be hypoxic. 
Because of differences in histology between head and neck cancers (squamous 
carcinoma) and rectal cancers (adenocarcinoma) and possible differences in 
excretion, we consider identifying ROIs in 50% of patients to be desirable and 
30% to be too low. 
 
Two criteria will be used for identifying hypoxia voxels. The first approach is the 
traditional method reported in the literature by the University of Washington 
group which defines hypoxia as tumor voxels for which the concentration ratio of 
FMISO between tumor to blood FMISO is 1.2 or greater, at a single late imaging 
time point. The second approach utilizes the kinetic profile of FMISO uptake and 
clearance from each tumor voxel. With this approach, hypoxic voxels are defined 
as those for which the uptake is slow and continuously rising vis-a-vis highly 
perfused regions where the initial uptake is high but continuously declining. One 
reason for employing the second approach is that there is evidence that a single 
late imaging time point can be ambiguous and not uniquely define the tumor 
hypoxic regions without knowledge of the history of the signal intensity to that 
voxel. 
As just mentioned, using both 18F-FMISO radioactivity concentration and kinetic 
uptake profile data in the tumor to signify a positive scan, we propose to evaluate 
the feasibility using a 2-stage design. In the first stage, 15 patients will receive an 
18F-FMISO PET scan. If 4 or fewer patients have identifiable ROIs, then the 
study will be stopped. If 5 or more have ROIs then an additional 15 patients at 
most will be scanned. 18F-FMISO imaging will be considered successful if ROIs 
are present in 13 or more of the 30 patients. However, even if the first 13 of 15 
patients scanned have identifiable ROIs, we will continue to scan up to 15 
additional patients in order to obtain a spectrum of hypoxic fraction versus 
treatment response. Pre-clinical studies are underway to determine the 
correspondence between the ROIs in the scan and hypoxia. 
 
In addition to visualizing these regions we want to determine their volume as a 
proportion of the entire tumor volume. If the ROIs correspond to hypoxia then 
the larger these proportions, the more hypoxic the tumor and potentially worse the 
prognosis. This data will provide preliminary information that could be used for a 

Memorial Sloan Kettering Cancer Center 
IRB Number: 07-151 A(10) 
Approval date: 06-Apr-2020 
-16- 
 
 
future trial with the 18F-FMISO imaging as a prognostic marker. If the imaging is 
successful, at least 13 patients will provide information for this objective which 
will be valuable preliminary data. 
 
Distribution of 18F-FMISO based on the pharmacokinetic data will be assessed 
using descriptive statistics (mean, standard deviation, etc.) and graphic tools. For 
instance, we will use both histograms and box plots to depict the data. 
 
The microdistribution of 18F-FMISO will be analyzed quantitatively through 
digital autoradiography. 
This design has 8% type I error and 80.4% power. 
 
 
15.0 
SUBJECT REGISTRATION AND RANDOMIZATION PROCEDURES 
15.1 
Research Participant Registration 
 
 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. During the registration process registering individuals will be 
required to complete a protocol specific Eligibility Checklist. The individual signing the 
Eligibility Checklist is confirming that the participant is eligible to enroll in the study. 
Study staff are responsible for ensuring that all institutional requirements necessary to 
enroll a participant to the study have been completed. See related Clinical Research 
Policy and Procedure #401 (Protocol Participant Registration). 
 
 
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. All 
research material from this study will be handled with the same confidentiality as 
patient’s other medical data. 
16.1 
Quality Assurance 
Weekly registration reports will be generated to monitor patient accruals and 
completeness of registration data. Routine data quality reports will be generated 
to assess missing data and inconsistencies. Accrual rates and extent and accuracy 
of evaluations and follow-up will be monitored periodically throughout the study 

Memorial Sloan Kettering Cancer Center 
IRB Number: 07-151 A(10) 
Approval date: 06-Apr-2020 
-17- 
 
 
period and potential problems will be brought to the attention of the study team 
for discussion and action 
 
Random-sample data quality and protocol compliance audits will be conducted by 
the study team, at a minimum of two times per year, more frequently if indicated. 
 
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 Clinical Research 
Administration. The MSKCC Data and Safety Monitoring Plans can be found on 
the MSKCC Intranet at: http://mskweb2.mskcc.org/irb/index.htm 
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. 
During the protocol development and review process, each protocol will be 
assessed for its level of risk and degree of monitoring required. Every type of 
protocol (e.g., NIH sponsored, in-house sponsored, industrial sponsored, NCI 
cooperative group, etc.) Will be addressed and the monitoring procedures will be 
established at the time of protocol activation 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
Risks of Study Participation: Potential risks as outlined in section 11.0 
(Toxicities and Side Effects) will be discussed with patients as part of the 
informed consent process, and patients will be watched closely for signs of 
adverse events. Whether or not a patient decides to participate in this study, he or 
she will receive the current standard of care for their specific disease site. 
 
Financial Costs to Patients: All diagnostic and therapeutic interventions except 
for the 18F-FMISO-PET scans, research blood draws, and digital 

Memorial Sloan Kettering Cancer Center 
IRB Number: 07-151 A(10) 
Approval date: 06-Apr-2020 
-18- 
 
 
autoradiography,are part of the current routine care of patients eligible for this 
study. A research grant will cover the cost of the 18F-FMISO-PET scans, research 
blood draws, and digital autoradiography. There are no additional financial costs 
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 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 

Memorial Sloan Kettering Cancer Center 
IRB Number: 07-151 A(10) 
Approval date: 06-Apr-2020 
-19- 
 
 
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 
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 

Memorial Sloan Kettering Cancer Center 
IRB Number: 07-151 A(10) 
Approval date: 06-Apr-2020 
-20- 
 
 
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. 
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 
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Approval date: 06-Apr-2020 
-21- 
 
 
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Approval date: 06-Apr-2020 
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Approval date: 06-Apr-2020 
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