Clinical trial NCT02471313
Conditions: Liver Cancer Liver Neoplasm Hepatocellular Carcinoma HCC
Keywords: Cross-Sectional Imaging Chemoembolization Radiation Therapy Tumor Hypoxia PET Imaging
Sponsor: National Institutes of Health Clinical Center (CC)
Start date: 2015-06-12; Completion date: 2018-03-07
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

\- Treatment for liver cancer can include surgery, transplant, and chemotherapy. It can also include other minimally invasive tumor treatments such as transarterial chemoembolization (TACE). TACE treatment for liver cancer helps control the cancer but is not considered a cure. Researchers want to learn more about the effects of TACE on liver tumors and surrounding tissue. To do this, they will use a positive emission test (PET) and a radioactive tracer called \[18F\] FMISO.

Objectives:

\- To see if \[18F\] FMISO is useful for evaluating what happens to liver tumors and surrounding tissue after TACE.

Eligibility:

\- People age 18 and older with liver cancer who have been approved to have TACE.

Design:

* Participants will meet with a study researcher to see if they can take part in the study.
* Participants will have TACE under a separate NCI protocol or at a hospital other than the NIH Clinical Center.
* Before and after TACE, participants will have a CT and MRI of the abdomen. For these scans, they will lie in a machine that takes pictures of their body. They will also have blood tests and a physical exam.
* The \[18F\] FMISO imaging study will be performed at NIH only.
* Participants will have an intravenous catheter placed in their arm (if they do not have one). The \[18F\] FMISO tracer will be injected.
* Participants will have PET-CT scans. Each scan will take about 30 minutes.
* Some participants will also have \[18F\] FMISO and PET-CT scans before TACE.
* As part of standard care for TACE, participants will have CT and MRI scans at regular intervals. This will evaluate tumor response.

Detailed description:
Background

* TACE is the standard therapy for inoperable primary liver cancers or tumor control prior to transplantation. The mechanisms for TACE s failure remains poorly understood.
* Although acute hypoxia and significant tumor necrosis occurs following TACE, the tumor adaptive response and localization for such have not been well characterized.
* Imaging tools using a hypoxia-specific tracer \[(18)F\] FMISO may help identify the pattern and distribution of acute post-TACE tumor hypoxia relative to demonstrated tumor progression.
* The primary hypothesis of this study states that tumor progression post-TACE arises from changes in tumor phenotype induced by treatment-related hypoxia superimposed on the dynamic process of underlying tumor hypoxia.

Objectives

-To determine the feasibility of hypoxic tumor identification despite relatively high liver background signal, and describe patterns of tumor hypoxia in the immediate post-TACE treatment period using PET imaging \[(18)F\] MISO uptake registered with cross-sectional imaging.

Eligibility

* Patients greater than or equal to 18 years with inoperable primary hepatic malignancy or hepatic-dominant metastatic-disease and be otherwise eligible to receive TACE treatment. Patients with hepatocellular carcinoma should have intermediate stage disease according to the BCLC staging system (Stage A4 or B).
* Patients must not have had chemotherapy- or radiation therapy to liver for at least 2 weeks prior to starting study treatments.
* Patients must not have an acute, critical illness.
* Patients must not be pregnant
* Able to understand and be willing to sign a written informed consent

Design

* Fifteen patients with primary or metastatic liver malignancy will be enrolled into this pilot, non-randomized, open study of the feasibility of using (18)F-fluoromisonidazole PET scanning to determine hypoxic tumor identification and localization, and to identify the pattern and distribution of acute post-TACE tumor hypoxia relative to demonstrated tumor progression.
* Twenty-four to seventy-two hours after standard of care TACE, patients will undergo

PET scanning using 0.1mCi/kg (maximum 10mCi) of (18)F-fluoromisonidazole \[(18)F\] MISO).

Arms: arm 1: Patients with primary hepatic malignancy who underwent \[18F\] FMISO PET Scan following transarterial chemoembolization (TACE) procedure
Interventions: intervention 1: [18F] FMISO
Intervention descriptions: intervention 1: \[18F\] Fluromisonidazole, 1 h-(3-\[18F\]-fluro-2hydroxyl-propy10-2-nitro-imidazaole is an investigational positron emission tomography (PET) radiopharmaceutical for injection and used to visualize hypoxia imaging agent. Each patient will receive up to 10 mCi of \[18F\] FMISO PET imaging post TACE procedure.

Protocol documents:
Prot_SAP_000.pdf: 
1 
Abbreviated Title: [18F] FMISO Imaging post TACE 
CC Protocol #: 15-CC-0137 C 
Version Date: 08/31/2016 
Title:  A Pilot Study of an Integrated Imaging Strategy to Phenotype Progression of Liver 
Tumors during and after Chemoembolization 
NIH Principal Investigator:   
      Elliot Levy, M.D. (A,B,C,D,E) 
Staff Clinician, Radiology & Imaging Sciences 
National Institutes of Health/Clinical Center 
9000 Rockville Pike 
Building 10, Rm. 1C367 
Bethesda, Maryland 20892 
T: 301-402-5368 F: 301-496-9933 
levyeb@cc.nih.gov 
NIH Lead Associate Investigators:  Bradford Wood, M.D. (A,B,E) 
Director, Center for Interventional Oncology 
Chief, Interventional Radiology 
National Institutes of Health/National Cancer Institute 
9000 Rockville Pike 
Building 10 Rm. 1C341 
Bethesda, Maryland, 20892 
MSC 1182 
Phone: 301-496-7739 
Fax: 301-451-5276 
BWood@cc.nih.gov 
NIH Associate Investigators: 
Peter Herscovitch, M.D. (A, F) 
Director, Positron Emission Tomography Department 
National Institutes of Health, Clinical Center 
9000 Rockville Pike 
Building 10 RM 1C495 
MSC 1180 
Phone: 301-451-4248 
Fax: 301-402-3521 
herscovitch@nih.gov 
Corina Millo, M.D. (A,B,E) 
Staff Clinician, Positron Emission Tomography Department 
National Institutes of Health, Clinical Center 
9000 Rockville Pike 
Building 10 RM 1C490 


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MSC 1180 
Phone: 301-402-4297 
Fax: 301-402-3521 
millocm@mail.nih.gov  
 
Tim Greten, M.D. (A,B, E) 
Thoracic and GI Malignancies Branch, CCR 
Head, Gastrointestinal Malignancy Section 
National Cancer Institute 
Building 10 RM 12N226 
Bethesda, Maryland 
Phone: 301-451-4723 
gretentf@mail.nih.gov  
 
Charisse Garcia, R.N. (A,B,C,E) 
Research Nurse Specialist 
Center for Interventional Oncology 
National Institutes of Health/National Cancer Institute  
9000 Rockville Pike 
Building 10 Rm. 1C364 
Bethesda, Maryland, 20892 
MSC 1182 
301-594-4511 
garciacr@cc.nih.gov  
 
Julie Peretti, R.N. (A,B,C,E) 
Research Nurse Specialist 
Center for Interventional Oncology 
National Institutes of Health/National Cancer Institute   
9000 Rockville Pike 
Building 10 Rm. 1C305 
MSC 1182 
Bethesda, Maryland, 20892 
301-451-3287 
jperetti@cc.nih.gov  
 
Victoria L. Anderson, MSN, FNP-C (A,B,C,E) 
Center for Interventional Oncology 
National Institutes of Health/Clinical Center 
9000 Rockville Pike 
Building 10 Rm. 1C305 
Bethesda, Maryland, 20892 
MSC 1182 
301-451-3288 


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Victoria.Anderson@nih.gov 
 
Referral Contact/  
Study Coordinator: 
Charisse Garcia, R.N. 
Research Nurse Specialist 
Center for Interventional Oncology 
National Institutes of Health/National Cancer Institute  
9000 Rockville Pike 
Building 10 Rm. 1C364 
Bethesda, Maryland, 20892 
MSC 1182 
301-594-4511 
garciacr@cc.nih.gov  
 
 
A. Obtain information by intervening or interacting with 
living individuals for research purposes 
B. Obtaining identifiable private information about 
living individuals 
C. Obtaining the voluntary informed consent of 
individuals to be subjects 
D. Makes decisions about subject eligibility 
E. Studying, interpreting, or analyzing identifiable 
private information or data/specimens for research 
purposes 
F. Studying, interpreting, or analyzing de-identified data 
or specimens for research purposes 
G. Some/all research activities performed outside NIH 
 
 
Investigational Agents:     
Drug Name: 
[18F] Fluromisonidazole, 1 H-(3-[18F]-fluro-2-
hydroxyl-propyl0-2-nitro-imidazole, [18F] FMISO   
IND Number: 
124706 
Sponsor: 
Dr. Elliot Levy 
Manufacturer: 
Cardinal Health 


Abbreviated Title: [ 18F]-FMISO Imaging Post TACE 
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PRÉCIS  
Background 
• TACE is the standard therapy for inoperable primary liver cancers or tumor control prior 
to transplantation. The mechanisms for TACE’s failure remains poorly understood.  
• Although acute hypoxia and significant tumor necrosis occurs following TACE, the 
tumor adaptive response and localization for such have not been well characterized. 
• Imaging tools using a hypoxia-specific tracer [18F] FMISO may help identify the pattern 
and distribution of acute post-TACE tumor hypoxia relative to demonstrated tumor 
progression.     
• The primary hypothesis of this study states that tumor progression post-TACE arises 
from changes in tumor phenotype induced by treatment-related hypoxia superimposed on 
the dynamic process of underlying tumor hypoxia.  
 
Objectives 
To determine the feasibility of hypoxic tumor identification despite relatively high liver 
background signal, and describe patterns of tumor hypoxia in the immediate post-TACE 
treatment period using PET imaging [18 F] MISO uptake registered with cross-sectional 
imaging. 
 
Eligibility 
• Patients ≥18 years of age with inoperable primary hepatic malignancy or hepatic-
dominant metastatic disease and be otherwise eligible to receive TACE treatment. 
Patients with hepatocellular carcinoma should have intermediate stage disease according 
to the BCLC staging system (Stage A4 or B). 
• Patients must not have had chemotherapy or radiation therapy to liver for at least 2 weeks 
prior to starting study treatments.   
• Patients must not have an acute, critical illness.  
• Patients must not be pregnant 
• Able to understand and be willing to sign a written informed consent 
 
Design 
• Fifteen patients with primary or metastatic liver malignancy will be enrolled into this 
pilot, non-randomized, open study of the feasibility of using 18F-fluoromisonidazole PET 
scanning to determine hypoxic tumor identification and localization, and to identify the 
pattern and distribution of acute post-TACE tumor hypoxia relative to demonstrated 
tumor progression.  
• Twenty-four to seventy-two hours after standard of care TACE, patients will undergo 
PET scanning using 0.1mCi/kg (maximum 10mCi) of 18F-fluoromisonidazole ([18F] 
MISO).  
 


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TABLE OF CONTENTS  
Précis ............................................................................................................................................... 5 
Table of Contents ............................................................................................................................ 6 
1 
INTRODUCTION .................................................................................................................. 8 
1.1 
Study Objectives .............................................................................................................. 8 
1.2 
Background and Rationale ............................................................................................... 8 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ......................................................... 9 
2.1 
Eligibility Criteria ............................................................................................................ 9 
2.2 
Screening Evaluation...................................................................................................... 11 
2.3 
Registration Procedures.................................................................................................. 11 
2.4 
Baseline Evaluation ........................................................................................................ 11 
3 
STUDY IMPLEMENTATION ............................................................................................ 12 
3.1 
Study Design .................................................................................................................. 12 
3.2 
Drug Administration ...................................................................................................... 12 
3.3 
Image Analysis ............................................................................................................... 13 
3.4 
Study Calendar ............................................................................................................... 13 
3.5 
Criteria for Removal from Protocol and Off Study Criteria .......................................... 14 
3.6 
Follow- up ...................................................................................................................... 15 
3.7 
Study Stopping Rules ..................................................................................................... 15 
4 
CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ............... 16 
5 
BIOSPECIMEN COLLECTION .......................................................................................... 16 
6 
DATA COLLECTION AND EVALUATION ..................................................................... 16 
6.1 
Data Collection ............................................................................................................... 16 
6.2 
Response Criteria ........................................................................................................... 16 
6.3 
Toxicity Criteria ............................................................................................................. 18 
7 
SAFETY REPORTING REQUIREMENTS/DATA&SAFETY MONITORING PLAN ... 18 
7.1 
Definitions ...................................................................................................................... 18 
7.2 
NCI-IRB Reporting ........................................................................................................ 20 
7.3 
IND Sponsor Reporting Criteria .................................................................................... 21 
7.4 
FDA Reporting Criteria .................................................................................................. 22 
7.5 
Data and Safety Monitoring Plan ................................................................................... 22 


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8 
STATISTICAL CONSIDERATIONS.................................................................................. 23 
9 
HUMAN SUBJECTS PROTECTIONS ............................................................................... 23 
9.1 
Rationale For Subject Selection ..................................................................................... 23 
9.2 
Participation of Children ................................................................................................ 23 
9.3 
Evaluation of Benefits and Risks/Discomforts .............................................................. 24 
9.4 
Consent Process and Documentation ............................................................................. 24 
10 PHARMACEUTICAL INFORMATION ............................................................................. 25 
10.1 
Source ......................................................................................................................... 25 
10.2 
Toxicity ....................................................................................................................... 26 
10.3 
Formulation and preparation ...................................................................................... 26 
10.4 
Dosing ......................................................................................................................... 27 
10.5 
Stability and Storage ................................................................................................... 27 
10.6 
Administration procedures ......................................................................................... 27 
10.7 
Incompatibilities ......................................................................................................... 27 
10.8 
Mechanism of Action ................................................................................................. 27 
11 REFERENCES ..................................................................................................................... 28 
12 APPENDICES ...................................................................................................................... 30 
12.1 
Appendix A: Performance Status Criteria .................................................................. 30 
12.2 
Appendix B: Eligibility Checklist .............................................................................. 31 
 
 
 


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1 
INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary Objective 
To determine the feasibility of hypoxic tumor identification despite relatively high liver 
background signal, and describe patterns of tumor hypoxia in the immediate post-TACE 
treatment period using PET imaging [18 F] MISO uptake registered with cross-sectional imaging. 
1.2 
BACKGROUND AND RATIONALE 
1.2.1 Hypoxia and the Tumor Microenvironment 
Hepatocellular carcinoma (HCC) is the sixth most common cancer across the globe and it 
represents the third most common cause of cancer related deaths.  HCC represents 90% of 
primary liver cancers. Liver tumor resection or liver transplantation, are first-line treatment 
options for HCC. Patients who are neither a candidate for surgery or transplantation can undergo 
minimally invasive procedures such as local ablation or chemoembolization. Often there is tumor 
progression despite these treatments1. The implications of tumor hypoxia following 
chemoembolization are unclear, although an association between hypoxia and more aggressive 
tumor phenotype is well known. As early as 1955, Thomlinson and Gray hypothesized that the 
presence of hypoxia may render lung cancers resistant to radiotherapy1. Tumor hypoxia occurs 
when oxygen consumption is out of balance with supply, as with reduced perfusion or diffusion-
limited oxygen delivery. Clinically relevant hypoxia is detected in approximately 50% of all 
solid tumors irrespective of their size and histological features 2. 
Durand and Aquino-Parsons3 studied tumor perfusion in a human xenograft tumor model and 
observed varying degrees of overlap of fluorescent staining or changes in fluorescence intensity 
corresponding to significant variations in tumor perfusion over relatively short periods of time.  
More recently more complex mechanisms resulting in significant fluctuations in red cell flux and 
tumor oxygenation have been implicated as potential determinants of tumor radio-resistance and 
chemo-resistance4,5. These fluctuations in tumor oxygenation may occur in cycles of extremely 
variable duration, on the order of minutes to hours, depending upon tumor type; various studies 
using different models have determined cycle durations of less than 2 cycles/minute6, cycles 
every 20-30minutes7 or 12 hours in patients imaged with PET hypoxia agents 8,9 tumor hypoxia 
and TACE therapy of liver tumors. 
TACE (transarterial chemoembolization) consists of the local transcatheter intrahepatic arterial 
delivery of chemotherapeutic agents combined with temporary occlusion of the artery(s) 
supplying the targeted neoplasm(s). The combination of acute ischemia and high concentrations 
of chemotherapeutic agent results in significant tumor necrosis, although the exact contribution 
of each mechanism remains poorly understood. Although TACE is considered palliative therapy 
for hepatic malignancy, TACE has been shown to prolong survival in patients with unresectable 
hepatocellular carcinoma (HCC) and is considered the standard of care for patients with 
unresectable intermediate HCC10.  The treatment has also been shown to have a measurable and 
statistically significant decrease in the size of treated lesions in metastatic liver disease11. The 
most common adverse effect of TACE is post-embolization syndrome, consisting of transient 
abdominal pain, nausea, vomiting, fever, and fatigue. Despite worldwide use of TACE for 


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unresectable HCC as well as chemo-refractory hepatic metastatic disease, TACE treatment 
failure is poorly understood.  Several factors may play a role in tumor progression despite 
TACE, including tumor resistance to chemotherapeutic drugs, which may be enhanced by 
hypoxia.  
Hepatic arterial embolization has been shown to yield discrete reductions in tumor  perfusion in a 
liver tumor model using TRIP MRI imaging12.  In the same tumor model, embolization with 40-
120μm microspheres was found to result in increased HIF-1a (hypoxia-inducible factor 1a) 
stabilitization13. These results confirm the degree and effect of acute embolization-related 
hypoxia, which represents a unique subset in the spectrum of the hypoxic tumor 
microenvironment; acute severe hypoxia is superimposed upon portions of normoxic and cycling 
hypoxic tumor by virtue of proximal occlusion of the arterial supply of the tumor(s).  Tumor 
tissue either undergoes ischemic necrosis or adaption to the acute hypoxic environment through 
hypoxia-induced gene expression and subsequent proliferation. 
1.2.2 
[18 F]-FMISO 
[18F] Fluromisonidazole, 1 H-(3-[18F]-fluro-2-hydroxyl-propyl0-2-nitro-imidazole, [18F] FMISO 
is an investigational PET radiopharmaceutical for injection and intended for use as tumor 
hypoxia imaging agent. [18F] FMISO possesses desirable qualities for evaluating hypoxia 
including an ideal partition coefficient and a relatively low required dose (≤ 10mCi). [18F] 
FMISO is reduced only in hypoxic tissues, resulting in hypoxia-specific intracellular 
accumulation.14 Imaging studies of head and neck as well as pancreatic tumor hypoxia using 
[18F] FMISO have been previously published15. This agent has shown no toxicity among 600 
patients who received at least four administrations. 
1.2.3 Rationale 
The primary hypothesis of this study states that tumor progression post-TACE results from 
changes in tumor phenotype induced by sublethal treatment-related hypoxia. The goal of the 
proposed pilot study is to test the feasibility of hypoxia imaging of the liver post-TACE.  Early 
imaging detection of residual hypoxic tumor acutely following TACE may ultimately correspond 
to undertreated tumor and could be used to optimize TACE outcomes with targeted 
combinational therapies.  
This pilot study will evaluate fifteen patients who will receive TACE therapy for primary or 
metastatic hepatic malignancy. They will undergo PET imaging of the liver with [18F] FMISO to: 
1) determine the feasibility of hypoxic tumor identification despite relatively high liver 
background signal, and 2) identify the pattern and distribution of acute post-TACE tumor 
hypoxia relative to demonstrated tumor progression despite therapy. Patients will be followed 
according to standard community practice with conventional cross-sectional imaging (CT and/or 
MRI) to confirm tumor progression. Image fusion analysis will be performed to determine 
degree of correlation between focal hypoxia and site(s) of progression. 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT  
2.1 
ELIGIBILITY CRITERIA 
2.1.1 Inclusion Criteria 


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2.1.1.1 Patients must have confirmed inoperable primary hepatic malignancy or hepatic 
dominant metastatic neoplastic disease evidenced by histology or cytology, or 
characteristic enhancement pattern on CT or MRI together with an abnormal serum 
alpha-fetoprotein >200mg/dl in the case of hepatocellular carcinoma.  
2.1.1.2 Patients with hepatocellular carcinoma should conform to intermediate stage disease 
according to the BCLC16 staging system (Stage A4 or B) and be otherwise eligible to 
receive TACE treatment17. 
2.1.1.3 Patients must have had no chemotherapy or radiotherapy to the liver  for their 
malignancy for at least 2 weeks (or until response can be adequately assessed) prior to 
treatment and must have recovered from all clinically significant side effects of 
therapeutic and diagnostic interventions. 
2.1.1.4 Serum creatinine less than or equal to 2.0 mg/dl unless the measured creatinine 
clearance is greater than 60ml/min 
2.1.1.5 Age >18 years  
2.1.1.6 Ability of subject to understand and willingness to sign a written informed consent 
document  
2.1.1.7 Patient must be able to lie still for the procedure 
2.1.1.8 ECOG status ≤ 2 
2.1.1.9 In addition, for patients receiving TACE outside NIH:  
• Patient must have physician willing to collaborate with NIH PI by providing 
required medical record and digital MR/ CT scan documentation pre and post 
TACE procedure.  
• Patient must be willing to sign an Authorization for the Release of Medical 
Information form.  
2.1.2 Exclusion Criteria 
2.1.2.1 Patients who have received prior TACE treatment  
2.1.2.2 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to misonidazole or other agents used in study.  
2.1.2.3 Patients with known brain metastases should be excluded from this clinical trial because 
of their poor prognosis and because they often develop progressive neurologic 
dysfunction that would confound the evaluation of neurologic and other adverse events.  
2.1.2.4 Uncontrolled intercurrent illness including, but not limited to ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 


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arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements.  
2.1.2.5 Patients of childbearing age must not be pregnant. The effects of [18F] FMISO on the 
developing human fetus are unknown.  Pregnancy is a contraindication for TACE. 
2.1.3 Recruitment Strategies 
Investigators will work closely to identify patients with colleagues at the NCI and in the local 
community including tumor board meetings to enlist their assistance in referrals. 
2.2 
SCREENING EVALUATION 
Patients may have TACE either at the NIH or the institution of their choice.   
The study procedure on this protocol is the FMISO scan, which will be performed at the NIH 
ONLY.  An eligibility checklist will be completed by the Principal Investigator during initial 
contact. An eligibility checklist including inclusion/exclusion criteria will be completed by 
referring physician for patients treated with TACE outside NIH or the Principal Investigator for 
patients treated with TACE at NIH. Referring physicians will fax or email a completed checklist 
at least one week prior to TACE. Following the Principal Investigator’s review of the returned 
checklist and confirmation of eligibility, patients will be contacted by a research staff member to 
1) discuss the study and answer questions, and 2) to offer enrollment into the protocol and 
schedule an appointment(s) for [18F] FMISO PET-CT scanning. 
The eligibility checklist will be reviewed with the patient when the patient provides informed 
consent and undergoes FMISO imaging. The consent process is described in section 9.4 and may 
occur over the telephone and by mail.  
2.3 
REGISTRATION PROCEDURES 
The Principal Investigator, along with key research personnel, will screen and enroll all eligible 
patients on the study. The screening and enrollment process will be documented in CRIS. All 
patients enrolled in the study will receive a unique patient identifier and will be entered in the 
study’s screening and enrollment logs which are kept in our research database. The study 
research database will be maintained in an electronic folder in a larger central shared drive with a 
secure password and Clinical Center network back-up, in accordance with NIH CC policy.  
2.4 
BASELINE EVALUATION 
No specific pre-procedure laboratory studies are required prior to FMISO administration. Pre-
TACE standard of care evaluation commonly occurs no more than four weeks prior to TACE 
and includes laboratory and imaging studies. These may include but not limited to: 
• Baseline CT and MRI of the abdomen  
• Tumor measurements 
• Baseline laboratories including an acute care, hepatic, and mineral panel, PT, aPTT, INR, 
CBC with differential, and AFP at outside institution.  
• Baseline history and physical exam  
• B-hCG (Urine or Serum) will be performed within 48 hours of FMISO imaging  


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3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
Fifteen patients with metastatic or primary hepatic malignancy will be enrolled to yield a 
minimum of ten evaluable patients. Prior to TACE, all patients will undergo conventional 
baseline imaging. The first five patients enrolled will receive a single dose of the study imaging 
agent (FMISO) post-TACE to determine imaging parameters and feasibility. Subsequent to the 
feasibility study, the remaining patients (#6-15) will receive the hypoxia imaging agent before 
and following TACE to determine changes in uptake pattern attributable to arterial embolization.  
Following TACE patients will be monitored according to standard of care until tumor 
progression is documented. Registration of functional and/or metabolic imaging demonstrating 
progression with immediate post-TACE hypoxia imaging will be performed for correlative 
analysis.  
3.1.1 TACE guidelines 
TACE will be performed per institution standard of care or separate protocol specifications. 
Documentation of the TACE procedure will be provided to the PI.   
3.1.2 FMISO Hypoxia Imaging 
Following screening and eligibility determination, patients will be contacted by a research staff 
member to offer enrollment into the protocol and schedule an appointment for [18F] FMISO 
PET-CT scanning. Consented patients are scheduled for [18F] FMISO PET-CT scanning. If the 
patient is not an inpatient at NIH CC, they should arrive approximately 1-2 hours before the 
appointed time for imaging, to go through outpatient admissions, and then to the PET scanning 
department to sign informed consent.  Once imaging is completed, the patient, based on their 
clinical condition, will return to the inpatient ward, transferred to a day hospital or clinic, or 
discharged home for further monitoring or instruction. 
3.1.3 Post TACE Cross-sectional Imaging for determination of progression despite TACE 
Patients will receive CT and MRI of the abdomen with contrast at 4-6 week intervals following 
TACE to detect tumor progression despite TACE per standard of care. Scanning interval may be 
increased to 3 months if stable disease is documented on at least two successive imaging studies. 
If these studies were done outside NIH CC, digital copies will be provided to PI at each post-
TACE interval for progression documentation and analysis (Section 3.3) 
3.2 
DRUG ADMINISTRATION  
[18F] FMISO imaging technique will be adapted from previously reported imaging studies for 
head and neck malignancies17 and pancreatic malignancy18. The [18F] FMISO will be 
administered intravenously at a dose of 0.1mCi/kg for hypoxia imaging. PET-CT imaging of the 
abdomen will be performed 120 minutes after injection. A repeat scan at 240 minutes after 
injection may be obtained if tumor-to background uptake is suboptimal and only if the patient’s 
condition permits. Each scan requires up to 30 minutes. Based upon previous reports, it is 
expected that [18F] FMISO uptake will peak within target liver tumor two hours following 
intravenous administration. Considerable background activity is expected in normal liver tissue, 
and techniques to maximize signal-to-noise activity in target tumors may include 1) 


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characterization of observed focal uptake relative to serum [18F] FMISO activity, where a tumor: 
serum ratio >1.2 has been considered indicative of hypoxia, or 2) delayed imaging up to 4 hours 
post-injection with subtraction techniques to identify focal tumoral uptake.  
3.3 
IMAGE ANALYSIS 
Feasibility of FMISO PET imaging post-TACE will be assessed by individually characterizing 
FMISO uptake in treated tumors as absent, background (equivalent to normal liver), or increased 
relative to liver background. Lesions demonstrating any increased activity compared to 
background liver will be further characterized as diffusely or focally increased activity.   
Changes in FMISO PET activity before and following TACE will be descriptively compared and 
change in peak SUV will be assessed as response to embolization. 
Individual liver tumors which demonstrate progression defined by increased size and/or 
enhancement will be evaluated for geographic FMISO uptake correlation. CT or MRI  images 
demonstrating progression will be registered with FMISO PET-CT images automatically using 
OncoNav software (developed at the Center of Interventional Oncology) to determine whether 
qualitatively increased or decreased FMISO uptake is observed in spatial relation to tumor 
progression.  
Increased FMISO activity which correlates positively with tumor progression will be further 
quantified using calculated standardized uptake values (SUV) or tumor-to- serum activity ratio in 
manually selected regions of interest (ROI).  
3.4 
STUDY CALENDAR  
Patients will be scheduled for pre-TACE imaging up to one week before TACE and post-TACE 
imaging 24 to 72 hours based on their clinical condition. Patients will sign the protocol consent 
prior to [18F] FMISO administration and imaging.  Per PET scanning protocols, patients will be 
NPO (≥4-6 hours) before actual scanning.  Patients will obtain standard of care post-TACE 
imaging by their primary oncology team, however, the research team may follow up, typically, 
but not required with clinic visits or phone calls. Follow up imaging and tumor measurements/s 
are the only research-related activities to be performed  until tumor progression, withdrawal from 
study or a new, non-TACE, treatment is indicated. If this follow-up occurs outside NIH CC, 
documentation must be provided to the study PI.  
 
Pre-[18F]FMISO 
PET Scan  
[18F] FMISO  
PET Scan4,5 
Standard of Care and 
Research 
follow up post TACE 3,4,7 
Informed consent1 
X 
 
 
[18F] FMISO dose 
approximately 10mCi4  
 
X 
 
Primary or metastatic 
malignant hepatic 
disease2 
X 
 
 
CT/ MRI4  
X 
 
X 


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Tumor measurements 4,8 
X 
 
X 
Demographics4 
X 
 
 
Medical history4  
X 
 
X 
Physical exam4 
X 
 
X 
Vital signs4  
X 
 
X 
Height4  
X 
 
 
Weight4  
X 
 
 
Creatinine4 
X 
 
 
B-hCG Urine or 
Serum3,6  
X 
 
 
Adverse event evaluation
 
X3 
X 
1. 
Informed consent must occur prior to any study specific procedure or scan. See also section 9.4  
2. 
In the absence of a pathological diagnosis of hepatocellular carcinoma, the diagnosis shall be made by the combination of serum alpha-
fetoprotein ≥ 200 mg/ml and CT or MRI of the liver showing an imaging appearance characteristic of hepatocellular carcinoma  
3. 
AE evaluation will be obtained within 24 hours post TACE FMISO injection.  
4. 
Patient must have physician willing to collaborate with NIH PI by providing required medical record and digital MR/ CT scan 
documentation pre and post TACE procedure. Imaging done outside NIH must be digitally provided to NIH for tumor measurement/ 
assessment  
5. 
NIH only  
6. 
FMISO imaging will be performed only post TACE in the first five consecutively enrolled patients and pre and post TACE in the 
remaining patients.  
7. 
Pregnancy test for women of childbearing potential. Test must be within 48 hours of PET scan  
8. 
Standard of care follow up post- TACE q 4-6 weeks. Scanning interval may be increased to 3 months if stable disease is documented on at 
least two successive imaging studies 
9. 
Imaging done outside NIH digitally provided to NIH for tumor measurement/assessment 
 
3.5 
 CRITERIA FOR REMOVAL FROM PROTOCOL AND OFF STUDY CRITERIA 
3.5.1 Off Treatment 
Patient will be considered “off treatment” 24 hours following post-TACE [18F] FMISO injection. 
No research-related follow up such as adverse event monitoring, will take place after this time 
period. 
3.5.2 General Off-Study Criteria 
• Inability to complete 18F-MISO imaging 
o Patients will be considered “unevaluable” for the study if [18F] FMISO imaging is 
incomplete or deficient and will be replaced (see Section 6.2.1). As an example,  
an FMISO scan which in the opinion of the Principal Investigator does not 
demonstrate hepatic uptake relative to background liver activity will be 
considered deficient and will not be included in the data analysis.  
• Patient decides to withdraw from the study  


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• Toxicity which prevents further imaging (e.g. renal dysfunction defined as serum 
creatinine >2.0mg/dl which precludes CT or MRI imaging) 
• Death 
• Progression of disease 
• Additional treatment of primary or metastatic  hepatic malignancy (i.e., transplantation, 
resection) 
The reason for study removal and the date the patient was removed must be recorded in the study 
database. 
3.6 
FOLLOW- UP 
Research-related follow up may be obtained outside NIH CC as part of routine pre- and post- 
TACE care. Patient must have physician willing to collaborate with NIH PI by providing 
required medical record and digital MR/ CT scan documentation pre and post TACE procedure. 
Imaging done outside NIH must be digitally provided to NIH for tumor measurement/ 
assessment. 
Primarily, after the patient is considered “off treatment”, research-related follow-up consists of 
standard of care post-TACE imaging which is q 4-6 weeks. Scanning interval may be increased 
to 3 months if stable disease is documented on at least two successive imaging studies  
Other typical, but not required, evaluations may also include clinical visits, phone calls from the 
research team, and laboratory testing.  
3.7 
STUDY STOPPING RULES 
Enrollment will be halted; IRB will be notified if: 
• Any grade 3 adverse event definitely attributed to [18F] FMISO (occurring within 24       
hours of injection) 
• Any grade 4 or grade 5 adverse event regardless of attribution 
• Patients not receiving TACE at NIH CC will be observed for adverse events according to 
one or more of the following: 
o Patient must have physician willing to collaborate with NIH PI by providing 
required medical record and digital MR/ CT scan documentation pre and post 
TACE procedure 
o patients will be provided with the PI’s contact information to report symptoms 
which could represent an adverse event, 
o telephone call from the PI’s designee on the day following the FMISO scan to 
document signs or symptoms 
• Patient(s) will be monitored until there is improvement or resolution of toxicity.   
• Following review and approval by the IRB study enrollment will resume.  
Enrollment will be limited to six patients if fewer than 2 patients demonstrate demonstrable 18F-
MISO uptake in liver tumors, consistent with diagnostic uptake of radiopharmaceutical in fewer 
than 30% of patients with liver cancer.  


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4 
CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES  
Patients will receive the standard of care supportive measures for patients undergoing DEB-
TACE and additional care at the discretion of their primary oncology team.  
5 
BIOSPECIMEN COLLECTION 
This protocol does not require bio-specimen collection.  If specimens are obtained, they will be 
done so on another NCI protocol. 
6 
DATA COLLECTION AND EVALUATION  
6.1 
 DATA COLLECTION 
Data collection for this study will include imaging data used to identify acute post-embolization 
tumor hypoxia, as well as conventional post-treatment imaging and measurement of tumor 
markers used to identify tumor progression despite therapy.  Other follow up data such as date of 
death will also be collected. The [18F] FMISO PET-CT imaging and post-treatment CT and MRI 
will be stored in PACS prior to image registration and analysis.  PET-CT and conventional CT 
images will be transferred to a workstation for registration analysis.  Identifiers will be removed 
from fused images for characterization of degree of overlap between documented tumor 
progression and acute post-treatment hypoxia. Imaging data including determination of response 
by mRECIST criteria as well as tumor marker levels will be collected in an Excel spreadsheet 
that will be stored in a password-protected PC kept in a secured office.  
Grade 2 events and higher will be recorded in the study database.  Grade 1 events will not be 
recorded or reported. 
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system and ensuring data accuracy, consistency and timeliness. The principal 
investigator, associate investigators/research nurses and/or a contracted data manager will assist 
with the data management efforts. Source data obtained during the conduct of the protocol will 
be kept in secure network drives or in approved alternative sites that comply with NIH security 
standards. Primary and final analyzed data will have identifiers so that research data can be 
attributed to an individual human subject participant. 
End of study procedures: Data will be stored according to HHS and FDA regulations as 
applicable.  
Loss or destruction of data: Should we become aware that a major breech in our plan to protect 
subject confidentiality and trial data has occurred, the IRB will be notified.  
6.2 
 RESPONSE CRITERIA 
6.2.1 Definitions 
6.2.1.1 Evaluable for toxicity  
All patients will be evaluable for toxicity from the time of their first treatment with [18F] FMISO 
up to 24 hours post injection and any adverse events including allergic reactions, FMISO 
extravasation, or any Grade 3 or greater AE within the 24-hour time frame post injection will be 
followed until resolution. 


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6.2.1.2 Evaluable for imaging response and inclusion in cohort of subjects   
Only those patients who have measurable disease present at baseline, and who have received 
baseline imaging (CT or MRI) and post TACE PET imaging with [18F] FMISO and at least one 
follow-up visit that includes CT or MRI. 
6.2.1.3 Target lesions  
Only measurable lesions targeted to undergo TACE will be evaluated. A sum of the diameters 
(longest for non-nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters. The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
6.2.2 
Methods for evaluation of measurable disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of TACE 
(cross-sectional imaging within four weeks of TACE treatment). 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging will include one or all of 
the following: CT (triple phase), MRI or PET scan.   
6.2.2.1 Conventional CT and MRI   
This guideline has defined measurability of lesions on CT scan based on the assumption that CT 
slice thickness is 5 mm or less.  If CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness. 
6.2.3 Response Criteria 
All of the patients who met the eligibility criteria (with the possible exception of those who could 
not undergo 18F-MISO imaging) should be included in the main analysis of the response to the 
imaging agent.  All conclusions should be based on all eligible patients. 
For the purposes of this study, patients with baseline CT or MRI and should be re-evaluated for 
response per standard of care approximately 4 to 6 weeks following TACE treatment with an 
abdominal CT and MRI. Scanning interval may be increased to 3 months instead of 4-6 weeks if 
stable disease is documented on at least two successive imaging studies obtained at the 4-6 week 
post-TACE interval.  
Response and progression of only targeted tumors will be evaluated in this study using the 
revised modified Response Evaluation Criteria in Solid Tumors (mRECIST) guidelines.19  
Complete 
Response (CR) 
Disappearance of any intratumoral arterial enhancement 
 
Partial Response 
(PR) 
At least 30% decrease in the sum of the diameters of viable 
(enhancement in the arterial phase) target lesions, taking the 
baseline sum of the diameters of target lesions 


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Stable Disease 
(SD) 
Any cases that do not qualify for either PR PD 
Progressive 
Disease (PD) 
An increase of at least 20% in the sum of the diameters of viable 
(enhancing) target lesion, taking as reference the smallest sum of 
the diameters of viable (enhancing) target lesions recorded since 
treatment started. 
 European Association for the Study of Liver, European Organization for Research and Treatment of Cancer. Journal of Hepatology, 2012 
56:908-943. 
Serum alpha-fetoprotein levels will be assessed and compared pre- and post-TACE per standard 
of care as a marker for tumor progression despite TACE. Cross-sectional and PET imaging will 
continue to be obtained at 4-6 week intervals until imaging evidence of disease progression is 
obtained and compared with FMISO imaging.    
6.3 
TOXICITY CRITERIA 
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study.  The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40).  
7 
SAFETY REPORTING REQUIREMENTS/DATA&SAFETY MONITORING PLAN 
7.1 
 DEFINITIONS 
7.1.1 Adverse Event 
An adverse event is defined as any reaction, side effect, or untoward event that occurs during the 
course of the clinical trial associated with the use of a drug in humans, whether or not the event 
is considered related to the treatment or clinically significant. For this study, AEs will include 
events reported by the patient, as well as clinically significant abnormal findings on physical 
examination or laboratory evaluation. A new illness, symptom, sign or clinically significant 
laboratory abnormality or worsening of a pre-existing condition or abnormality is considered an 
AE. All AEs must be recorded on the AE case report form unless otherwise noted above in 
Section 6.1. 
All AEs, including clinically significant abnormal findings on laboratory evaluations, regardless 
of severity, will be followed until return to baseline or stabilization of event.  Patients will be 
evaluable for toxicity due to [18F] MISO for a period of one day after radiopharmaceutical 
administration (exceeding 10 half-lives of the radiopharmaceutical).  An abnormal laboratory 
value will be considered an AE if the laboratory abnormality is characterized by any of the 
following: 
• 
Results in discontinuation from the study 
• 
Is associated with clinical signs or symptoms  


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• 
Requires treatment or any other therapeutic intervention 
• 
Is associated with death or another serious adverse event, including hospitalization.  
• 
Is judged by the Investigator to be of significant clinical impact 
• 
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome. 
7.1.2 Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug.  
7.1.3 Unexpected adverse reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been observed; or, 
if an investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. 
“Unexpected” also refers to adverse events or suspected adverse reactions that are mentioned in 
the investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation. 
7.1.4 Serious  
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious 
Adverse Event or if it compromises the safety, welfare or rights of subjects or others. 
7.1.5 Serious Adverse Event 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
• 
Death, 
• 
A life-threatening adverse drug experience 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect. 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based 
upon appropriate 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. 


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7.1.6 Disability 
A substantial disruption of a person’s ability to conduct normal life functions. 
7.1.7 Life-threatening adverse drug experience 
Any adverse event or suspected adverse reaction that places the patient or subject, in the view of 
the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction that had it occurred in a more severe form, might have caused death. 
7.1.8 Protocol Deviation (NIH Definition) 
Any change, divergence, or departure from the IRB-approved research protocol.  
7.1.9 Non-compliance (NIH Definition) 
The failure to comply with applicable NIH Human Research Protections Program (HRPP) 
policies, IRB requirements, or regulatory requirements for the protection of human research 
subjects. 
7.1.10  Unanticipated Problem 
Any incident, experience, or outcome that: 
•  Is unexpected in terms of nature, severity, or frequency in relation to  
(a) the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents, and 
(b) the characteristics of the subject population being studied; AND 
• Is related or possibly related to participation in the research; AND 
• Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
7.2 
NCI-IRB REPORTING 
7.2.1 NCI-IRB Expedited Reporting of Unanticipated Problems and Deaths 
The Protocol PI will report to the NCI-IRB: 
• All deaths, except deaths due to progressive disease  
• All Protocol Deviations 
• All Unanticipated Problems 
• All non-compliance 
 
Reports must be received by the NCI-IRB within 7 working days of PI awareness via iRIS. 
7.2.2 NCI Requirements for PI Reporting at Continuing Review 
The protocol PI will report to the NCI-IRB:  


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1. A summary of all protocol deviations in a tabular format to include the date the deviation 
occurred, a brief description of the deviation and any corrective action. 
2. A summary of any instances of non-compliance 
3. A tabular summary of the following adverse events: 
• All Grade 2 unexpected events that are possibly, probably or definitely related to the 
research;  
• All Grade 3 and 4 events that are possibly, probably or definitely related to the 
research;  
• All Grade 5 events regardless of attribution;  
• All Serious Events regardless of attribution.  
NOTE: Grade 1 events are not required to be reported.  
7.2.3 NCI-IRB Reporting of IND Safety Reports 
Only IND Safety Reports that meet the definition of an unanticipated problem will need to be 
reported to the NCI IRB. 
7.3 
IND SPONSOR REPORTING CRITERIA  
An investigator must immediately report to the sponsor, using the mandatory MedWatch form 
3500a, any serious adverse event, whether or not considered drug related, including those listed 
in the protocol or investigator brochure and must include an assessment of whether there is a 
reasonable possibility that the drug caused the event.  
Study endpoints that are serious adverse events (e.g. all-cause mortality) must be reported in 
accordance with the protocol unless there is evidence suggesting a causal relationship between 
the drug and the event (e.g. death from anaphylaxis).  In that case, the investigator must 
immediately report the death to the sponsor. 
Events will be submitted to the IND Sponsor/ Investigator Dr. Elliot Levy at: 
National Institutes of Health/Clinical Center 
9000 Rockville Pike 
Building 10, Rm. 1C367 
Bethesda, Maryland 20892 
T: 301-402-5368 
F: 301-496-9933 
levyeb@cc.nih.gov 


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7.4 
FDA REPORTING CRITERIA 
7.4.1 IND Safety Reports to the FDA (Refer to 21 CFR 312.32) 
The Sponsor will notify the FDA of any unexpected fatal or life-threatening suspected adverse 
reactions as soon as possible but no later than 7 calendar days of initial receipt of the information 
using the MedWatch Form 3500a.  
The Sponsor is also responsible for reporting any:  
• suspected adverse reaction that is both serious and unexpected 
• any findings from clinical, epidemiological, or pooled analysis of multiple studies or any 
findings from animal or in vitro testing that suggest a significant risk in humans exposed 
to the drug 
• clinically important increase in the rate of a serious suspected adverse reaction over that 
listed in the protocol or investigator brochure  
to the FDA and to all investigators no later than 15 calendar days after determining that the 
information qualifies for reporting using the MedWatch Form 3500a. If FDA requests any 
additional data or information, the sponsor must submit it to the FDA as soon as possible, but no 
later than 15 calendars days after receiving the request.  
7.4.2 FDA Annual Reports (Refer to 21 CFR 312.33) 
The study Sponsor will submit a brief report annually of the progress of the trial within 60 days 
of the anniversary date that the IND went into effect as indicated in 21CFR 312.33, and any 
associated FDA correspondences regarding the IND annual report.  
7.5 
DATA AND SAFETY MONITORING PLAN 
7.5.1 Principal Investigator/Research Team  
The clinical research team will meet regularly while patients remain in the study. Any adverse 
event, toxicity, and imaging evaluations will be discussed as a group. 
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Adverse events will be reported as required above. Any safety concerns, 
new information that might affect either the ethical and or scientific conduct of the trial, or 
protocol deviations will be immediately reported to the IRB using iRIS and to the Sponsor.  
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
7.5.2 Sponsor Monitoring Plan 
Dr. Virginia Guptil, Clinical Center Clinical Research Quality Coordinator from the Office of the 
Deputy Director for Clinical Care will monitor this study and will not be affiliated in any way 
with the trial conduct. She is qualified by training and experience to monitor the progress of 
clinical trials.  


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All enrolled patients will have follow up evaluations per standard of care until they show disease 
progression, withdrawal from the study or begin another treatment. All patients will have 100% 
source document verification done.  Additional monitoring activities will include: adherence to 
protocol specified study eligibility, treatment plans, data collection for safety and efficacy, 
reporting and time frames of adverse events to the NCI IRB and FDA, and informed consent 
requirements. Written reports will be generated in response to the monitoring activities and 
submitted to the Principal investigator and Clinical Director of the NIH Clinical Center.  
8 
STATISTICAL CONSIDERATIONS   
The study is a proof of concept protocol. It aims to determine the feasibility of acute hypoxia 
imaging of the liver following TACE.  Power and significance calculations are not applicable to 
this small sample feasibility study.  
9 
HUMAN SUBJECTS PROTECTIONS  
9.1 
RATIONALE FOR SUBJECT SELECTION 
The study will seek to enroll both adult men and women who meet eligibility criteria, including 
whites, non-whites, and minorities. Transarterial chemoembolization is considered standard of 
care for unresectable hepatic malignancy where the dominant tumor burden is found in the liver. 
Patients with primary or metastatic liver tumors will be eligible for treatment with hepatic 
chemoembolization and study-defined imaging. Hepatocellular carcinoma is variously ranked as 
the fourth to sixth most common neoplasm worldwide. Annualized rate among men is 22.1 per 
100,000 and 8.5 women per 100,000 population has been described worldwide. 
Cholangiocarcinoma most commonly occurs in females over 60 years of age, and the incidence 
in western countries is 2-6 cases per 100,000 people per year. 
Patients who may be unable to comprehend the study requirements and associated risks may not 
be able to adequately appreciate the relatively small potential benefit which might be derived 
from participation. These patients will be considered ineligible to enroll.  
9.2 
PARTICIPATION OF CHILDREN 
The most common types of liver cancer in children include hepatoblastoma, hepatocellular 
carcinoma, undifferentiated embryonal sarcoma of the liver, and infantile choriorcarcinoma of 
the liver. Hepatocelluar carcinoma and hepatoblastoma can be cured by surgical resection. Other 
treatments for childhood liver cancer include chemotherapy, radiation therapy, and percutaneous 
ethanol injection. HCC and hepatoblastoma can be treated with chemoembolization followed by 
resection. The aim of the proposed study is to describe an imaging phenotype of liver tumor 
recurrence in patients undergoing chemoembolization for unresectable liver cancer; 
chemoembolization treatment in children is intended to downsize or downstage tumors to 
achieve resectability, and study-related imaging and tissue sampling is not indicated in this 
clinical scenario.  


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9.3 
EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
9.3.1 Risk of IND agent 
Although there has been no reported toxicity for the [18F] FMISO dose required for hypoxia 
imaging two potential risks common to radiopharmaceutical imaging agents that are possible 
include:  
• Allergic reaction  
• Extravasation of the imaging agent into the skin\subcutaneous tissue from Intravenous 
infiltration. 
9.3.1.1 Risk of Radiation from Research Procedure 
This research study involves exposure to radiation from PET-CT with 10mCi of [18F] FMISO. 
According to the Investigator’s Brochure, the calculated total body dose for a 70kg man injected 
with 3.7 MBq/kg (~10mCi) is 0.013 mGy/MBq.  Effective dose ranges from 0.013-0.014 
mSv/MBq. The highest organ-specific radiation dose is observed in the bladder wall, likely due 
to urinary excretion of ~3% of the administered dose. The mean effective CT radiation dose 
associated with the PET-CT study should be less than 6 mSv.  The amount of radiation patients 
will receive in this study is below the guideline of 5 rem/per year allowed for research subjects 
by the NIH Radiation Safety Committee.  The average person in the United States receives a 
radiation exposure of 0.3 rem/per year from natural sources, such as the sun, outer space, and the 
earth's air and soil.   
The NIH Radiation Safety Committee will review this protocol to assure it meets standard safety 
criteria. 
9.3.2 Potential benefits to subjects 
There is no direct benefit to patients. Their participation advances our understanding of the 
disease and the imaging tools. 
9.4 
CONSENT PROCESS AND DOCUMENTATION 
9.4.1 NIH TACE-treated study subjects  
The Principal Investigators or associate investigators will explain the rationale of the study, 
including the study plan, the risks and potential benefits, when the patient is also evaluated for 
TACE in the outpatient clinic or prior to TACE administration. Patients will be given ample time 
to process the consent, ask questions and be counseled adequately to satisfy all parties. Patients 
will have an opportunity to deliberate at home and provide witnessed telephone consent after the 
initial intake visit. 
The informed consent document will be sent to the subject.  An explanation of the study will be 
provided over the telephone after the subject has had the opportunity to read the consent form.  
The subject will sign and date the informed consent. A witness to the subject’s signature will 
sign and date the consent. 
The original informed consent document will be sent back to the consenting investigator who 
will sign and date the consent form with the date the consent was obtained via telephone.   


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A fully executed copy will be returned via mail for the subject’s records. 
The informed consent process will be documented on a progress note by the consenting 
investigator and a copy of the informed consent document and note will be kept in the subject’s 
research record. 
9.4.2 Referral center TACE-treated study subjects 
The treating physician(s) will inform the patient about the study, and the Principal Investigator or 
associate investigator will explain the study in detail, including the study plan, risks, and 
potential benefits either by telephone or in person before the TACE procedure is performed or 
before or at the time of the planned FMISO injection and scan. If consent is to be obtained prior 
to the TACE procedure, the informed consent document can be sent to the subject. In any case 
the consent form will be witnessed as described above. A fully executed copy will be provided to 
the study subject, and the process will be documented in CRIS as a progress note. A copy of the 
consent document and progress note will be included in the subject’s research record.  
 
9.4.3 Informed consent of non-English speaking subjects: 
If there is an unexpected enrollment of a research participant for whom there is no translated 
extant IRB approved consent document, the principal investigator and/or those authorized to 
obtain informed consent will use the Short Form Oral Consent Process as described in MAS 
Policy M77-2, OSHRP SOP 12, 45 CFR 46.117 (b) (2), 21 CFR 50.27 (b) (2).  The summary 
that will be used is the English version of the extant IRB approved consent document.  Signed 
copies of both the English version of the consent and the translated short form will be given to 
the subject or their legally authorized representative and the signed original will be filed in the 
medical record. 
 
Unless the PI is fluent in the prospective subject’s language, an interpreter will be present to 
facilitate the conversation. Preferably someone who is independent of the subject (i.e., not a 
family member) will assist in presenting information and obtaining consent. Whenever possible, 
interpreters will be provided copies of the relevant consent documents well before the consent 
conversation with the subject (24 to 48 hours if possible).  
 
We request prospective IRB approval of the use of the short form process for non-English 
speaking subjects and will notify the IRB at the time of continuing review of the frequency of the 
use of the Short Form. 
 
10 PHARMACEUTICAL INFORMATION   
10.1 SOURCE 
Doses of drug will be obtained from Cardinal Health’s manufacturing site located at 7051 
Muirkirk Meadows Drive, Suite K Beltsville, MD 20705. Acquired doses will be maintained in 


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the Clinical Center PET department and dosing will be managed by the PET department research 
pharmacist, Luke Park (301-496-1090, LPark@cc.nih.gov). 
10.2 TOXICITY  
10.2.1 Animal Toxicity Studies 
Studies done in male Sprague-Dawley rats to evaluate [18F] FMISO  neurotoxicity showed that at 
high doses of 300 to 400mg/kg the rats after motor testing showed signs of neurotoxicity 
including ataxia, tremors, vocalizations, circling, head jerking and hyperactivity, all of which 
resolved.20 No evidence of peripheral nerve toxicity was reported. 
10.2.2 Human Toxicity Studies 
There are no studies published which report toxicity of [18F] FMISO in humans. The 
Investigator’s Brochure for [18F] FMISO provides a list (Table 8) of human imaging studies from 
1994 to the present which includes a total of approximately 600 patients who received up to 4 
doses of FMISO (3-30mCi) and PET scanning and for which no adverse events  are identified.20 
Studies of MISO toxicity have shown that side effects may be observed at doses 5 to 6 times 
greater than needed for PET scanning. Oral MISO in oral doses ranging from 4-10g has been 
used to enhance cytotoxicity of radiotherapy in patients with advanced cancer.  All patients 
experienced some degree of nausea, vomiting and anorexia for 24 hours. The severity of the 
nausea and vomiting was correlative to a high MISO dose. Studies where MISO was given in 
multiple doses reported peripheral neuropathy in doses of 3-5g/m.2, 21 
Two fatalities are reported in patients with advanced cancer who died with convulsions. One 
patient had consumed 51g in 6 doses over 17 days and the other consumed 16g in 2 doses over 3 
days.22 
The planned dose of [18F] FMISO will be approximately 10mCi which includes approximately 
15 micrograms of misonidazole which is unlikely to be associated with MISO-related side 
effects.  
10.3 FORMULATION AND PREPARATION  
[18F] fluoromisionidazole,1 H -1-(3-[18F]-fluoro-2-hydroxy-propyl)-2-nitroimidazoleor [18F] 
FMISO, cross referencing  Cancer Imaging Program IND 76,042  
[18F] FMISO is a radiolabeled imaging agent that has been used for investigating tumor hypoxia 
with positron emission tomography (PET). [18F] FMISO is an investigational agent and the 
Cancer Imaging Program Cardinal Health partnering with the American College of Radiology 
Imaging Network supplies [18F] FMISO. The PET scanning department will procure and 
maintain the [18F] FMISO. Cardinal Health is the only entity to have a drug master file with the 
Food and Drug Administration (FDA) to produce this imaging agent.  
[18F] FMISO is the only active ingredient and it is dissolved in a solution of ≤ 10ml of 95% 
isotonic saline, 5% ethanol (v:v). The drug solution is stored in a gray butyl septum sealed, 
sterile, pyrogen-free glass vial with a 12 hour expiration. The vials are to be stored at room 
temperature.   


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10.4 DOSING 
≤10mCi  
10.5 STABILITY AND STORAGE  
[18F] FMISO has a 12 hour shelf life and is to be stored at room temperature. The Clinical 
Center PET department pharmacy will procure, store, dose and prepare for injection. 
10.6 ADMINISTRATION PROCEDURES 
[18F] FMISO is given intravenously. The prepared dose is then given by the staff of the CC, PET 
department per their standard guidelines. 
10.7 INCOMPATIBILITIES   
[18F] FMISO is a small water-soluble molecule with a molecular weight of 189.14 Daltons. It has 
an octanol-water partial coefficient of 0.41, so that it would be expected to reflect plasma flow as 
an inert freely-difusable tracer immediately after injection, but later images should reflect its 
tissue partition coefficient in normotoxic tissues.  
10.8 MECHANISM OF ACTION 
[18F] FMISO has a nearly ideal partition coefficient and when reduced by hypoxia, binds 
covalently to cellular molecules at rates that are inversely proportional to intracellular oxygen 
concentrations, rather than by downstream biochemical reactions.  FMISO is not trapped in 
necrotic tissue because mitochondrial electron transport is absent. The normal route of 
elimination is renal. 
*The rotarod test is widely used to evaluate the motor coordination of rodents, and is especially sensitive in 
detecting cerebellar dysfunction 
 
 


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11 REFERENCES  
1. 
Thomlinson RH, Gray LH. The histological structure of some human lung cancers and 
the possible implications for radiotherapy. British journal of cancer 1955;9:539-49. 
2. 
Vaupel P, Mayer A, Hockel M. Tumor hypoxia and malignant progression. Methods in 
enzymology 2004;381:335-54. 
3. 
Durand RE, Aquino-Parsons C. Non-constant tumour blood flow--implications for 
therapy. Acta Oncol 2001;40:862-9. 
4. 
Dewhirst MW. Relationships between cycling hypoxia, HIF-1, angiogenesis and 
oxidative stress. Radiation research 2009;172:653-65. 
5. 
Dewhirst MW, Cao Y, Moeller B. Cycling hypoxia and free radicals regulate 
angiogenesis and radiotherapy response. Nature reviews Cancer 2008;8:425-37. 
6. 
Braun RD, Lanzen JL, Dewhirst MW. Fourier analysis of fluctuations of oxygen tension 
and blood flow in R3230Ac tumors and muscle in rats. The American journal of physiology 
1999;277:H551-68. 
7. 
Trotter MJ, Chaplin DJ, Durand RE, Olive PL. The use of fluorescent probes to identify 
regions of transient perfusion in murine tumors. International journal of radiation oncology, 
biology, physics 1989;16:931-4. 
8. 
Ljungkvist AS, Bussink J, Kaanders JH, van der Kogel AJ. Dynamics of tumor hypoxia 
measured with bioreductive hypoxic cell markers. Radiation research 2007;167:127-45. 
9. 
Nehmeh SA, Lee NY, Schroder H, et al. Reproducibility of intratumor distribution of 
(18)F-fluoromisonidazole in head and neck cancer. International journal of radiation oncology, 
biology, physics 2008;70:235-42. 
10. 
Lammer J, Malagari K, Vogl T, et al. Prospective randomized study of doxorubicin-
eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the 
PRECISION V study. Cardiovascular and interventional radiology 2010;33:41-52. 
11. 
Artinyan A, Nelson R, Soriano P, et al. Treatment response to transcatheter arterial 
embolization and chemoembolization in primary and metastatic tumors of the liver. HPB 
(Oxford) 2008;10:396-404. 
12. 
Wang D, Bangash AK, Rhee TK, et al. Liver tumors: monitoring embolization in rabbits 
with VX2 tumors--transcatheter intraarterial first-pass perfusion MR imaging. Radiology 
2007;245:130-9. 
13. 
Rhee TK, Young JY, Larson AC, et al. Effect of transcatheter arterial embolization on 
levels of hypoxia-inducible factor-1alpha in rabbit VX2 liver tumors. Journal of vascular and 
interventional radiology : JVIR 2007;18:639-45. 
14. 
McClelland RA. Molecular interactions and biological effects of the products of 
reduction of nitroimidazoles.  Selective activation of drugs by redox processes: Springer; 
1990:125-36. 


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Version Date: 08/31/2016 
 
 
29 
 
15. 
Prekeges JL, Rasey JS, Grunbaum Z, Krohn KH. Reduction of fluoromisonidazole, a new 
imaging agent for hypoxia. Biochemical pharmacology 1991;42:2387-95. 
16. 
Barcelona Clinic Liver Cancer (BCLC) Staging and Treatment Strategy includes Nexavar 
for advanced HCC. 2014. (Accessed September 04, 2014, at https://www.nexavar-
us.com/scripts/pages/en/health-care-provider/hcc/treatment-plan/how-nexavar-fits-in/bclc-
guidelines/.) 
17. 
Padhani AR, Krohn KA, Lewis JS, Alber M. Imaging oxygenation of human tumours. 
European radiology 2007;17:861-72. 
18. 
Segard T, Robins PD, Yusoff IF, et al. Detection of hypoxia with 18F-fluoromisonidazole 
(18F-FMISO) PET/CT in suspected or proven pancreatic cancer. Clinical nuclear medicine 
2013;38:1-6. 
19. 
Cancer EAftSotLEOfRaTo. EASL–EORTC Clinical Practice Guidelines: management of 
hepatocellular carcinoma. Journal of hepatology 2012;56:908-43. 
20. 
[18F] fluoromisonidazole, 1H-1-(3-[18F]-fluoro-2-hydroxy-propyl)-2-nitro-imidazole, 
[18F]FMISO. 2013. at http://www.acrin.org/Portals/0/Protocols/6697/6697_FMISO%20-
IB_Edition5_ReleaseDate-February5,%202013.pdf.) 
21. 
Saunders ME, Dische S, Anderson P, Flockhart IR. The neurotoxicity of misonidazole 
and its relationship to dose, half-life and concentration in the serum. The British journal of 
cancer Supplement 1978;3:268-70. 
22. 
Dische S, Saunders M, Flockhart I, Lee M, Anderson P. Misonidazole—a drug for trial in 
radiotherapy and oncology. International Journal of Radiation Oncology* Biology* Physics 
1979;5:851-60. 
 


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30 
 
 
 
12 APPENDICES 
12.1 APPENDIX A: PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, 
able to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 


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12.2 APPENDIX B: ELIGIBILITY CHECKLIST 
Eligibility Criteria 
 
Confirmation Checklist 
Patient Name 
 
First _____________ Last_______________ 
Primary diagnosis 
 
□ Cytology 
For patients with HCC: 
□ Tumor enhancement + AFP >200 
□ BCLC Stage A4   □ BCLC Stage B 
CT + MRI  
 
□ 
Age 
 
□ >18 years _________ 
History & Physical Exam  
 
□ including intercurrent illnesses 
Height & Weight 
 
□ 
ECOG Status  
 
□ ≤ 2 ________ 
Serum creatinine 
 
□ <2.0 mg/dl _________ (unless creatinine clearance 
greater than 60ml/min) 
B-hCG Urine or Serum  
 
□ Negative 
Eligible for TACE 
 
□  
No prior TACE 
 
□ 
No biologic, chemo-, or 
radiotherapy for at least two 
weeks prior to enrollment 
 
□ 
Able to understand and sign an 
informed consent document 
 
□ 
Able to lie still and cooperate 
for PET scan 
 
□ 
No pregnancy 
 
□ 
Prior allergic reaction to 
misonidazole or iodinated 
contrast 
 
□ 
No concurrent investigational 
agents 
 
□ 
Known brain metastases 
 
□ 


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32 
 
A Pilot Study of an Integrated Imaging Strategy to Phenotype Progression of Liver Tumors 
during and after Chemoembolization 
 
The completed eligibility checklist should be received by the Principal Investigator not less than 
one week prior to TACE AND at least 48 hours prior to FMISO imaging. 
 
Office: (301) 402-5368     Fax: (301) 496-9933    Email: levyeb@cc.nih.gov 
Address: National Institutes of Health 
 
   Department of Radiology and Imaging Sciences 
 
   10 Center Drive, Rm 1C367 
 
    Bethesda, Maryland 20814-9692 
 
Uncontrolled intercurrent illness 
 
□ (active infection, CHF, angina, cardiac arrhythmia, 
psychiatric/social