Clinical trial NCT03648073
Conditions: Hepatocellular Carcinoma
Sponsor: University of Alabama at Birmingham
Start date: 2019-01-30; Completion date: 2022-02-03
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
There is great need for new therapeutic options for patients with hepatocellular carcinoma (HCC). This proposal will assess the feasibility of a novel theranostic approach to HCC using \[68Ga\]DOTATATE, a recently approved positron emission tomography (PET) ligand for imaging somatostatin receptor (SSTR) positive tumors. In this study, we will use \[68Ga\]DOTATATE to determine the percentage of HCCs that express adequate levels of SSTR for treatment with targeted radionuclide therapy (TRT) using the therapeutic SSTR ligand \[177Lu\]DOTATATE. This radionuclide therapy was FDA approved in January 2018 for treating neuroendocrine tumors (NETs) arising from the gastrointestinal tract, but its use in HCC has not yet been explored. In the long term, we envision using \[68Ga\]DOTATATE-PET to identify HCC patients with adequate SSTR expression for TRT using \[177Lu\]DOTATATE.

Liver transplantation is the only curative therapy for HCC and is an option for a selected subset of HCC patients. For those who are not candidates for transplantation, locoregional therapies with limited efficacy are available such as percutaneous ablation, arterial chemoembolization, and Y-90 microsphere radionuclide therapies. There are few options for patients who progress or are not candidates for these therapies. The first line systemic therapy is sorafenib, a tyrosine kinase inhibitor. Sorafenib is often not well tolerated due to its side effects and there is need for additional systemic treatments. Multiple tissue-based studies demonstrate SSTR positivity in 20-50% of HCCs.\[1-3\] However, the fraction of HCCs have high enough levels of SSTR for \[177Lu\]DOTATATE therapy has not yet been assessed. This research plan is a critical prerequisite for determining the feasibility of this theranostic approach to treating HCC. If we obtain positive results, these data will be critical for designing a combined imaging and therapeutic study in HCC using DOTATATE.

Detailed description:

Arms: arm 1: \[68Ga\]DOTATATE-PET/MRI in Hepatocellular Carcinoma
Interventions: intervention 1: [68Ga]DOTATATE-PET/MRI
Intervention descriptions: intervention 1: \[68Ga\]DOTATATE-PET/MRI

Protocol documents:
Prot_SAP_001.pdf: 
1 
Official Title: [68Ga]DOTATATE-PET/MRI in Hepatocellular Carcinoma to Assess the Feasibility 
of Targeted Radionuclide Therapy with Somatostatin Receptor Ligands  
 
NCT Number: NCT03648073 
 
Document Date: September 27, 2018 
 
 


2 
Comprehensive Cancer Center 
University of Alabama at Birmingham 
Birmingham, Alabama 
 
Protocol UAB 18-107: 
[68Ga]DOTATATE-PET/MRI in Hepatocellular Carcinoma to Assess 
the Feasibility of Targeted Radionuclide Therapy with Somatostatin 
Receptor Ligands 
 
TABLE OF CONTENTS 
 
 
 
 
 
1.0 
INTRODUCTION AND STUDY RATIONALE 
 
 
 
 
2.0 
STUDY OBJECTIVES 
 
 
 
 
3.0 
INVESTIGATIONAL PLAN 
 
 
 
 
4.0 
STUDY PROCEDURES 
 
 
 
 
5.0 
STUDY PARAMETERS 
 
 
 
 
6.0 
STATISTICAL CONSIDERATIONS 
 
 
 
 
7.0 
REFERENCES 
 
 
 
 
 
Samuel J. Galgano, M.D 
Assistant Professor 
Advanced Accelerator Applications & 
University of Alabama at Birmingham 
UAB Comprehensive Cancer Center 
 
Department of Radiology 
 
Study Supported By 
619 19th St S, JTN 325 
 
Birmingham, AL  35249 
UAB 
 
 
 
 
 
Tel (205-996-2802); Fax (205-996-0059) 
Study Sponsor 
 
Principal Investigator 
 
 
Ga-68 DOTATATE 
 
 
Study Agent 
 
 
 
Pending 
 
 
IND Number 
 
Jonathan McConathy, MD, PhD, Ravi Paluri, MD, 
 
Yufeng Li, PhD 
 
Rojymon Jacob, MD, Andrew McDonald, MD, 
 
Biostatistician 
Jared White, MD, Stephen Gray, MD, Devin Eckhoff, MD, 
Kristin Porter, MD, PhD 
 
Sub-Investigators 
 
 
 
Marianne Vetrano, April Riddle 
 
April Riddle 
 
Research Nurse Coordinator 
Data Coordinator 
 
 
 


3 
TABLE OF CONTENTS 
 
 
1.0 
Introduction and Study Rationale ..........................................................  
4 
1.1 
Overview ....................................................................................................  
4 
1.2 
Background and Rationale ......................................................................  
4 
2.0 
Objectives ...................................................................................................  
5 
3.0 
Investigational Plan ..................................................................................  
6 
3.1 
Study Design ..............................................................................................  
6 
3.2 
Study Population .......................................................................................  
6 
3.3 
Inclusion Criteria ......................................................................................  
6 
3.4 
Exclusion Criteria .....................................................................................  
6 
3.5 
Withdrawal Criteria .................................................................................  
6 
3.6 
Replacement of Patients ...........................................................................  
6 
3.7 
Study Duration ..........................................................................................  
7 
3.8 
Safety Monitoring .....................................................................................  
7 
3.8.1 
Data and Safety Monitoring Plan ...........................................................  
7 
3.8.2 
Ethical Considerations .............................................................................  
7 
4.0 
Study Procedures ......................................................................................  
7 
4.1 
Informed Consent Procedure ..................................................................  
7 
4.2 
Patient Registration ..................................................................................  
7 
4.3 
Initiation of Study .....................................................................................  
8 
4.4 
Drug Information ......................................................................................  
8 
4.5 
Patient Assessment....................................................................................  
8 
4.6 
Imaging Information ................................................................................  
8 
4.6.1 
[68Ga]DOTATATE PET Preparation and Injection ...........................  
8 
4.6.2 
[68Ga]DOTATATE PET/MRI Protocol.................................................  
8 
4.6.3 
[68Ga]DOTATATE PET/CT Protocol ...................................................  
9 
4.6.4 
PET/MRI Imaging Interpretation and Storage ...................................  
9 
4.6.5 
Safety Monitoring .....................................................................................  
10 
4.6.6 
Patient Follow-Up .....................................................................................  
10 
5.0 
Study Parameters ......................................................................................  
10 
5.1 
Primary Endpoints....................................................................................  
10 
5.2 
Study Termination ....................................................................................  
10 
6.0 
Statistical Considerations ........................................................................  
10 
6.1 
Study Design ..............................................................................................  
10 
6.2 
Sample Size Determination......................................................................  
11 
6.3 
Definition of Analyzed Study Population ..............................................  
11 
6.4 
Analysis .......................................................................................................  
11 
6.5 
Data and Safety Monitoring Plan ...........................................................  
11 
6.5.1 
Pre-study Documentation ........................................................................  
11 
6.5.2 
Institutional Review Board Approval ....................................................  
11 
6.5.3 
Informed Consent .....................................................................................  
11 
6.5.4 
Changes in Protocol ..................................................................................  
12 
6.5.5 
Adverse Event Reporting.........................................................................  
12 
6.5.5.1 
General Definitions ...................................................................................  
13 


4 
6.5.5.2 
AE Reporting Requirements ...................................................................  
14 
6.5.5.3 
CAEPR/ASAE for [68Ga]DOTATATE..................................................  
14 
6.5.5.4 
Potential but Unexpected AE for [68Ga]DOTATATE ........................  
14 
6.5.5.5 
Review of Safety Information .................................................................  
15 
6.5.5.6 
Adverse Event Reporting.........................................................................  
16 
6.5.5.7 
Expedited Adverse Reaction Reporting Guidelines ............................  
17 
6.5.6 
Protection of Privacy ................................................................................  
17 
6.6 
Data Management .....................................................................................  
17 
7.0 
References ..................................................................................................  
18 
 
 
 


5 
1.0 
Introduction and Study Rationale 
 
1.1 
Overview 
 
There is great need for new therapeutic options for patients with hepatocellular carcinoma 
(HCC). This study will assess the feasibility of a novel theranostic approach to 
hepatocellular carcinoma (HCC) using [68Ga]DOTATATE, a recently FDA-approved 
positron emission tomography (PET) ligand for imaging somatostatin receptor (SSTR) 
positive tumors. This PET tracer is in routine clinical use for neuroendocrine tumors (NET) 
but to our knowledge has not been systematically applied to HCC. The objective of this 
study is to measure the frequency of SSTR positivity in hepatocellular carcinoma using 
[68Ga]DOTATATE-PET. We hypothesize that [68Ga]DOTATATE-PET will be positive in 
at least 20% of patients with HCC. If this current study shows a substantial fraction HCCs 
have moderate to high SSTR levels based on PET imaging, this result would justify future 
studies evaluating  targeted radionuclide therapy (TRT) with the therapeutic SSTR ligand 
[177Lu]DOTATATE which was recently FDA approved for treating SSTR-positive NETs 
arising from the gastrointestinal tract. 
 
Study objective: Determine the frequency of somatostatin receptor positivity in 
hepatocellular carcinoma using [68Ga]DOTATATE-PET 
 
Hypothesis: [68Ga]DOTATATE PET will be positive in at least 20% of patients with 
hepatocellular carcinoma (HCC).  
 
In this study, patients with treatment-naïve HCC (n=15) and patients with previously 
treated HCC being referred for systemic chemotherapy and/or best supportive care (n=15) 
will be enrolled. Patients will undergo a single whole body [68Ga]DOTATATE-PET/MRI 
to assess SSTR positivity of their HCCs. The percentage of patients with HCCs showing 
activity in their HCC greater than liver and/or spleen will be calculated.  
 
1.2 
Background and Rationale 
 
HCC is the most common type of liver cancer and frequently arises in the background of 
hepatic cirrhosis. HCC and other liver cancers accounted for an estimated 40,710 cases and 
28,920 deaths in the United States in 2017.[1] The five-year survival for patients with liver 
cancer confined to the liver is estimated at 31.1%, but prognosis for tumors that spread 
outside of the liver is much worse with 10.7% five-year survival for patients with regional 
lymph node metastases and 2.8% for patients with distant metastases.[1] The definitive 
treatment for HCC is liver transplantation, but frequently patients do not choose to undergo 
transplantation or are deemed ineligible. In recent years, locoregional therapies for HCC 
have 
become increasingly utilized, including 
transarterial chemoembolization, 
percutaneous ablation, external beam radiation, and radioembolization with 90Y-labeled 
microspheres. These treatments are frequently utilized as a bridge to transplantation, but 
can also be used for definitive therapy for HCC. However, once the tumor has been found 
to spread beyond the liver and adjacent lymph nodes, few systemic treatment options 
remain available to patients. The first systemic treatment option for HCC was sorafenib, a 
tyrosine kinase inhibitor which was approved in 2007 for treatment of advanced HCC 


6 
following a trial that demonstrated a 44% improvement in median overall survival when 
compared to placebo.[2] However, sorafenib is frequently not well tolerated by patients 
with side effects experienced by approximately 64.9% of patients, with diarrhea, hand-
foot-skin reaction, nausea, and fatigue being the most common.[3] As a result, in 2017 a 
second-line tyrosine kinase inhibitor (regorafenib) was approved in patients with advanced 
HCC who have been unable to tolerate or progressed on sorafenib.  
 
[68Ga]DOTATATE (tradename NETSPOT) is a peptide-based radiopharmaceutical for 
positron emission tomography (PET) that was approved for clinical use in the United States 
in 2016 for the evaluation of somatostatin receptor (SSTR)-positive neuroendocrine tumors 
(NETs). This PET tracer binds to SSTRs on the surface of tumor cells with the highest 
affinity for the SSTR2 receptor which is overexpressed in neuroendocrine tumors. In 
patients with metastatic NETs, somatostatin analogues (e.g. octreotide and lantreotide) are 
a mainstay in control of symptoms, but do not treat the underlying metastatic disease. In 
2018, the FDA approved a therapeutic analogue of DOTATATE ([177Lu]DOTATATE, 
tradename Lutathera)  for the treatment of SSTR-positive gastroenteropancreatic NETs. A 
key concept is that [68Ga]DOTATATE-PET is used to evaluate metastatic NETs for SSTR 
expression and use this information to select potential candidates for [177Lu]DOTATATE 
therapy. This theranostic approach can potentially be applied to other tumors that express 
adequate levels of SSTR.  
 
SSTR expression has previously been demonstrated in the setting of HCC to varying 
degrees. A study of 53 resected HCCs demonstrated that membrane SSTR2 was reliably 
detected in HCC and could serve as a potential therapeutic target.[4] Multiple tissue-based 
studies demonstrate SSTR positivity in 20-50% of HCCs.[4-6] Additionally, SSTR2 
expression in HCC was positively correlated with cytokeratin 19-9 expression, serum 
alpha-fetoprotein level, and poor differentiation, all of which are poor prognostic markers 
for patients with HCC.[4, 7, 8] Additional studies have confirmed SSTR expression in 
HCC with varying distributions of the SSTR receptor subtype expression.[5, 6] However, 
the fraction of HCCs have high enough levels of SSTR for [177Lu]DOTATATE therapy 
has not yet been assessed. Therefore, it is our aim to use [68Ga]DOTATATE-PET/MRI to 
assess tumor SSTR expression in patients with HCC before and after locoregional therapy. 
This research plan is a critical prerequisite for determining the feasibility of this theranostic 
approach to treating HCC. If we obtain positive results, these data will be critical for 
designing a combined imaging and therapeutic study in HCC using DOTATATE. 
 
2.0 
Study Objectives 
 
Specific Aim 1: Determine the frequency of somatostatin receptor positivity in 
hepatocellular carcinoma using [68Ga]DOTATATE-PET 
 
Hypothesis 1: [68Ga]DOTATATE PET will be positive in at least 20% of patients with 
hepatocellular carcinoma (HCC).  
 
 
Liver transplantation is the only curative therapy for HCC and is an option for a selected 
subset of HCC patients. For those who are not candidates for transplantation, 
locoregional therapies with limited efficacy are available such as percutaneous ablation, 


7 
arterial chemoembolization, and Y-90 microsphere radionuclide therapies. There are few 
options for patients who progress or are not candidates for these therapies. The first line 
systemic therapy is sorafenib, a tyrosine kinase inhibitor. Sorafenib is often not well 
tolerated due to its side effects and there is need for additional systemic treatments.  
 
3.0 
Investigational Plan 
 
3.1 
Study Design 
The project will be a pilot prospective IRB-approved HIPAA-compliant study that will 
enroll 15 patients with untreated HCC and 15 patients with previously treated HCC. 
These patients will be identified at weekly multidisciplinary hepatobiliary conference in 
collaboration with liver transplant surgery, interventional radiology, diagnostic radiology, 
hematology/oncology, gastroenterology, and radiation oncology. Patients will undergo 
standard-of-care treatment based on recommendations of hepatobiliary tumor board. The 
preferred imaging modality will be PET/MRI, owing to its superior soft tissue 
characterization of the liver and abdominal soft tissues when compared to non-contrast 
CT performed for PET/CT. However, understanding that patients may have large volume 
ascites or claustrophobia, PET/CT may be utilized as an alternative in select patients at 
the discretion of the Principal Investigator. The study will be performed within 4 weeks 
of most recent conventional anatomic imaging with either CT or MRI to minimize the 
potential to alter clinical management on the basis of the CT or MRI portion of the 
research examination. 
 
3.2 
Study Population 
 Patients with treatment naïve hepatocellular carcinoma and patients with 
previously treated hepatocellular carcinoma being referred for systemic 
chemotherapy and/or best supportive care 
 
3.3 
Inclusion Criteria 
 Known diagnosis of hepatocellular carcinoma, either by imaging criteria 
or pathology on biopsy 
 Standard of care liver MRI or CT demonstrating viable HCC based on 
arterial contrast enhancement measuring at least 1.5 cm in largest axial 
dimension  
 
3.4 
Exclusion Criteria 
 History of neuroendocrine tumor or other SSTR-positive tumor 
 Current treatment with octreotide or lantreotide 
 Interval locoregional therapy or new systemic therapy between standard of 
care liver MRI or CT study showing viable HCC and [68Ga]DOTATATE-
PET 
 
3.5 
Withdrawal Criteria 
 Given that enrollment in this study will involve a single imaging exam, no 
withdrawal criteria will be used 


8 
 Patient charts will be followed for 12 months following PET to evaluate 
for outcomes 
 
3.6 
Replacement of Patients 
 Given that enrollment in this study will involve a single imaging exam, no 
replacement of patients will be used 
 
3.7 
Study Duration 
 Study enrollment and imaging will take place over 12 months 
 
3.8 
Safety Monitoring 
 
3.8.1 Data and Safety Monitoring Plan 
 
Patients will be informed of the extent to which their confidential health 
information generated from this study may be used for research purposes. 
Following this discussion, they will be asked to sign the HIPAA form and 
informed consent documents. The original signed document will become part of 
the patient’s medical records, and each patient will receive a copy of the signed 
document. The use and disclosure of protected health information will be limited 
to the individuals described in the informed consent document. PET/MRI and 
PET/CT scans will be loaded into a separate password-protected image storage 
system that will not appear on the PACS utilized in clinical practice.  
 
3.8.2 Ethical Considerations 
 
Given that the study involves a single imaging session with either PET/MRI or 
PET/CT and the expected age of the enrolled adult patients, ethical concerns 
regarding additional radiation exposure are minimal. If an unexpected potentially 
medically important finding is detected through participation in this study, the 
referring provider will be notified of the results to consider pursuing additional 
imaging or other diagnostic procedure. 
 
4.0 
Study Procedures 
 
4.1 
Informed Consent Procedure 
All participants must be provided a consent form describing the study with sufficient 
information for each participant to make an informed decision regarding their 
participation.  Participants must sign the IRB-approved informed consent form prior to 
participation in any study specific procedure.  The participant must receive a copy of the 
signed and dated consent document.  The original signed copy of the consent document 
must be retained in the medical record or research file.  
4.2 
Patient Registration 
Enrollment in the study will be available after the patient has been seen by their treating 
physician at UAB. The majority of these patients are expected to be seen in Liver 
Transplant clinic. However, all patients that meet enrollment criteria are eligible. 


9 
Registration in the study will be performed by a research coordinator from the UAB 
Department of Radiology. Participation in the study is voluntary and choosing not to 
participate will not affect patient care in any way. 
 
4.3 
Initiation of Study 
The PET tracer [68Ga]DOTATATE is FDA-approved for gastroenteropancreatic 
neuroendocrine tumors and routinely produced for standard-of-care clinical PET through 
the UAB Cyclotron Facility and Radiopharmacy. The preparation of [68Ga]DOTATATE 
for this study will be identical to the procedure used for producing clinical dosages. 
Additionally, UAB currently is performing clinical [68Ga]DOTATATE-PET scans, 
including PET/CT and PET/MRI. Therefore, the study can be initiated immediately 
following institutional and IRB approval. 
 
4.4 
Drug Information 
[68Ga]DOTATATE is a radiolabeled peptide-based analogue of octreotide that is FDA-
approved PET imaging agent for use in patients with gastroenteropancreatic 
neuroendocrine tumors. The radiotracer targets somatostatin receptors with highest 
affinity for SSTR2, which has been shown to be overexpressesd in hepatocellular 
carcinoma. The dosage of radiotracer administered to the patient is an intravenous 
weight-based dose of 2 MBq/kg (0.054 mCi/kg) up to a dose of 200 MBq (5.4 mCi). This 
results in an effective dose of up to 4.2 mSv (420 mrem) to the patient, which is equal to 
1.4 years of natural background radiation exposure (3 mSv/yr).  
 
4.5 
Patient Assessment 
Identification and workup of patients prior to potential enrollment in the study will follow 
standard-of-care procedures per the treating physician (hepatobiliary surgery, radiation 
oncology, etc.). If a patient is determined to be eligible for the study, the research 
coordinator in this study will be asked to come to the clinic to discuss potential 
enrollment. 
 
4.6 
Imaging Information 
4.6.1 [68Ga]DOTATATE PET Preparation and Injection 
The injected dose will be an intravenous weight-based dose of 2 MBq/kg (0.054 
mCi/kg) up to a dose of 200 MBq (5.4 mCi). The patient will be instructed to 
undergo standard patient preparation prior to DOTATATE PET/CT or PET/MRI. 
PET imaging will begin approximately 60 minutes following injection.  
 
4.6.2 [68Ga]DOTATATE PET/MRI Protocol 
 
Whole body imaging 
Positron Emission Tomography Acquisition: The patient will be placed on the 
PET/MRI scanner in the supine position. Initial localizer images will be obtained.  
Subsequently, static whole body images will be acquired from pelvis to skull base 
utilizing approximately eight 14 cm detector beds for 3-5 minute acquisitions per 
bed position. Correction for randoms, scatter, attenuation and reconstructions will 
be performed per the manufacturer’s recommendations.  


10 
 
Whole Body and Liver MRI: Sequences performed will include MR attenuation 
correction (MRAC), axial and coronal T2 single shot fast spin echo and whole body 
Dixon-derived sequences. 
 
Following whole body PET imaging, a routine MRI of the liver will be performed 
at UAB in the PET/MRI scanner per institutional protocol with and without the use 
of gadoteridol (Prohance) intravenous contrast via a weight-based dose of 0.2 
ml/kg. An additional static abdominal PET acquisition will be performed 
concurrently. 
 
The study protocol has been submitted to, reviewed, and approved by the UAB 
Radiation Safety Committee (OH&S Project 18-154). 
 
The entire study is expected to take 60-90 minutes to acquire, with the whole body 
portion taking approximately 30 minutes and dedicated liver portion taking 
approximately 30 minutes. 
 
4.6.3 [68Ga]DOTATATE PET/CT Protocol 
If the patient is unable to complete the PET/MRI scan or the patient is felt to be a 
suboptimal candidate for PET/MRI (due to large volume ascites, surgical clip 
artifacts, etc.), the patient will undergo whole body PET/CT. 
 
Whole body imaging 
Positron Emission Tomography Acquisition: The patient will be placed on the 
PET/CT scanner in the supine position. Initial localizer images will be obtained.  
Subsequently, static whole body CT images will be acquired from pelvis to skull 
base utilizing approximately eight 14 cm detector beds for 3-5 minute acquisitions 
per bed position. Correction for randoms, scatter, attenuation and reconstructions 
will be performed per the manufacturer’s recommendations.  
 
Whole Body CT: Patient will undergo a noncontrast non-optimized CT for 
anatomic localization of PET findings per institutional protocol (kVp 140, mA 
400). The estimated dose of the CT exam is approximately 6 mSv, equal to 
approximately two years of background radiation. 
 
The study protocol has been submitted to, reviewed, and approved by the UAB 
Radiation Safety Committee. 
 
4.6.4 PET/CT and PET/MRI Imaging Interpretation and Storage 
Images from the PET/CT and PET/MRI will be anonymized and subsequently 
stored and reviewed using a commercially available software package (MIM 
Encore, Cleveland, OH). The PET and whole body MRI studies will not be 
available in the UAB PACS system. This is in an effort to blind the treating 
physicians from making clinical decisions on an experimental imaging technique. 
The liver MRI images will be sent to clinical PACS and the medical record as part 


11 
of standard-of-care imaging and can be used in the clinical-decision making 
process. No formal interpretation will be generated for the [68Ga]DOTATATE-PET 
or whole body MRI portion of the study. 
 
PET/CT and PET/MRI images will be interpreted by board certified physicians 
specialized in molecular imaging and abdominal imaging. Images will initially be 
interpreted as positive or negative for SSTR-positive HCC. HCC lesions will be 
considered SSTR positive for the purposes of this study if they have higher 
[68Ga]DOTATATE activity than adjacent liver not involved by HCC. The amount 
of [68Ga]DOTATATE binding for intrahepatic HCCs will be further characterized  
based on visual analysis as less than skeletal muscle (no binding), higher than 
skeletal muscle but less than or equal to adjacent liver (low binding), higher than 
adjacent liver but less than spleen (moderate binding) or equal to or greater than 
spleen (high binding). For patients with SSTR-positive HCC and positive 
[68Ga]DOTATATE PET, intrahepatic and extrahepatic disease will be assessed on 
MRI/CT alone first, with confidence in interpretation rated on a 1-5 scale (1 = 
negative, 5 definite). Following this, fused PET/CT or PET/MRI images will be 
assessed and rated on the same 1-5 scale. 
 
4.6.5 Safety Monitoring 
Vital signs will be assessed immediately before and after injection of 
[68Ga]DOTATATE (HR and supine BP).  Patients will be monitored for adverse 
events during injection and after completion of the imaging study   Additionally, 
patient’s vitals (HR and supine BP) will be checked at the completion of the 
imaging study prior to leaving the imaging center. 
 
4.6.6 Patient Follow-Up 
Patients will be instructed to contact the UAB Department of Radiology Advanced 
Imaging Facility if there are any concerns about delayed side effects related to the 
study radiotracer.  Patients will be seen in the clinic if there are any concerning 
study related adverse events requiring further evaluation. 
 
5.0 
Study Parameters 
5.1 
Primary Endpoint 
- 
Percentage of patients with moderate to high binding of [68Ga]DOTATATE on PET 
examination 
- 
Concordance between [68Ga]DOTATATE PET results and liver MRI results 
 
5.2 
Study Termination 
The study will stop enrolling patients once the target number has been reached. 
 
6.0 
Statistical Considerations 
6.1 
Study Design 
This is a prospective pilot trial to determine the potential use of [68Ga]DOTATATE PET 
for patients with hepatocellular carcinoma to assess feasibility of targeted radionuclide 
therapy with somatostatin receptor ligands. The primary objective of this study is to 


12 
determine if a sufficient fraction (20% or greater) of HCC seen on conventional anatomic 
imaging demonstrates levels of somatostatin receptor expression to result in a positive 
DOTATATE PET scan. If a sufficient fraction of patients demonstrate positive 
DOTATATE PET scans, this study could serve as the basis for a subsequent therapeutic 
clinical trial with [177Lu]DOTATATE.  
 
6.2 
Sample Size Justification 
As this is a pilot feasibility study, no formal hypothesis will be testing, and thus no power 
analysis was performed. The primary objective is to determine the frequency of 
somatostatin receptor positivity in hepatocellular carcinoma using [68Ga]DOTATATE-
PET. In this study, patients with treatment-naïve HCC (n=15) and patients with previously 
treated HCC being referred for systemic chemotherapy and/or best supportive care (n=15) 
will be enrolled through the UAB Hepatobiliary Tumor Board in order to estimate the 
percentage of patients with moderate to high binding of [68Ga]DOTATATE on PET 
examinations. Patients will undergo a single whole body [68Ga]DOTATATE-PET/MRI or 
PET/CT to assess SSTR positivity of their HCCs. If a sufficient fraction (20% or greater) 
of HCC seen on conventional anatomic imaging demonstrate levels of somatostatin 
receptor expression to result in a positive DOTATATE PET scan, a subsequent therapeutic 
clinical trial with [177Lu]DOTATATE will be carried out. With a total of 30 patients 
enrolled, the estimated  
percentage of positive binding of [68Ga]DOTATATE will have two-sided 95% confidence 
intervals (CI) from 7.7% ≤ p ≤ 38.6% using the Clopper-Pearson (exact) method assuming 
at least 20% positive binding occurs.  Although the confidence interval will be wide for 
each subgroup, e.g. treatment-naïve HCC or previously treated HCC with n=15 (95% CI 
4.3% ≤ p ≤ 48.1%), it will provide early evidence if the [68Ga]DOTATATE binding will 
be affected by prior treatment and/or stage of disaese.  
 
 
6.3 
Definition of Analyzed Study Population 
All patients who underwent a [68Ga]DOTATATE-PET/MRI or PET/CT scan will be 
included in the analysis.  
 
6.4 
Statistical Analysis Plan 
This study will largely be exploratory and descriptive. For all clinical and histological 
evaluations as well as imaging parameters, we will generate summary tabulations of the 
number of observations, mean, standard deviation, median, minimum, and maximum for 
continuous variables, and the frequency and percentage for categorical variables. Analyses 
will be primarily descriptive and graphical in nature. The count, and percentage of patients 
with HCCs showing activity in their HCC greater than liver and/or spleen will be estimated 
using Clopper-Pearson (exact) method along with two-sided 95% CI. The estimation will 
be provided for all 30 patients first, and then by treatment-naïve or not. 
 
Concordance between [68Ga]DOTATATE PET results and liver MRI results for patients 
with SSTR-positive HCC and positive [68Ga]DOTATATE PET, intrahepatic and 
extrahepatic disease will be assessed on MRI/CT alone first, with confidence in 
interpretation rated on a 1-5 scale (1 = negative, 5 definite). Following this, fused 
PET/CT or PET/MRI images will be assessed and rated on the same 1-5 scale. Scale 3-4 


13 
is defined as positive. The agreement(concordance)  between nominal (e.g. scale 1-5) or 
binary  outcome (positive or negative) of [68Ga]DOTATATE PET results and liver MRI 
results will be assessed using  Cohen’s kappa coefficients with one-side 95% confidence 
intervals. Based on values of Cohen’s kappa,   the agreement will be considered as poor 
(>0.2), fair (0.21-0.40), modrate (0.41-0.60), good (0.61-0.80), and very good (0.81-1.0) 
(Dtsch Arztebl Int. Concordance Analysis .2011 Jul; 108(30): 515–521. PMID: 
21904584). Bland-Altman diagrams will be used to evaluate agreement for other 
continuous imaging variables between these two methods. All statistical analysis will be 
carried on SAS v9.4. 
 
6.5 
Data and Safety Monitoring Plan 
6.5.1 Pre-Study Documentation 
This study will be conducted in accordance with the ethical principles that have 
their origin in the Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); 
consistent with GCP and all applicable regulatory requirements. 
Before initiating this trial, the Investigator will have written and dated approval 
from the Institutional Review Board for the protocol, written informed consent 
form, subject recruitment materials, and any other written information to be 
provided to subjects before any protocol related procedures are performed on any 
subjects.   
 
The clinical investigation will not begin until either FDA has determined that the 
study under the Investigational Drug Application (IND) is allowed to proceed or 
the Investigator has received a letter from FDA stating that the study is exempt 
from IND requirements. 
6.5.2 Institutional Review Board Approval 
The protocol, the proposed informed consent form, and all forms of participant 
information related to the study (e.g. advertisements used to recruit participants) 
will be reviewed and approved by the UAB IRB. Prior to obtaining IRB approval, 
the protocol must be approved by the by the UAB Comprehensive Cancer Center 
Protocol Review Committee (PRC).  The initial protocol and all protocol 
amendments must be approved by the IRB prior to implementation.   
6.5.3 Informed Consent 
All participants must be provided a consent form describing the study with 
sufficient information for each participant to make an informed decision regarding 
their participation.  Participants must sign the IRB-approved informed consent form 
prior to participation in any study specific procedure.  The participant must receive 
a copy of the signed and dated consent document.  The original signed copy of the 
consent document must be retained in the medical record or research file.  
6.5.4 Changes in the Protocol 
Once the protocol has been approved by the UAB IRB, any changes to the protocol 
must be documented in the form of an amendment.  The amendment must be signed 
by the Investigator and approved by the IRB prior to implementation.   
 
If it becomes necessary to alter the protocol to eliminate an immediate hazard to 
patients, an amendment may be implemented prior to IRB approval.  In this 
circumstance, however, the Investigator must then notify the IRB in writing within 
five (5) working days after implementation.   


14 
6.5.5 Adverse Event Reporting 
As with many IV administered agents, [68Ga]DOTATATE could cause an allergic 
reaction that could potentially pose a threat to life (anaphylaxis).  This has not been 
observed in human exposure to date.  Reasonable precautions will be taken, 
consistent with normal radiologic and clinical facility practice.  The patient will be 
monitored until the PET procedure is completed, and trained personnel and 
emergency equipment will be available per facility standards. 
 
Qualifying Adverse Events (AEs), including Serious Adverse Events (SAEs), as 
defined herein, will be reported via the FDA Adverse Event Expedited Reporting 
System (AERS). For the [68Ga]DOTATATE IND we will report adverse events 
based on the FDA final rule for IND safety reporting requirements under 21 CFR 
part 312 published on September 29, 2010 and implemented on March 28, 2011.  
This investigational study is not a BA or BE study so 21 CFR part 320 is not 
applicable.  Adverse events will also be reported to the UAB IRB according to their 
requirements. 
 
Reporting of Serious Adverse Events (SAEs) to Advanced Accelerator 
Applications (AAA): In addition to reporting of SAEs to the responsible IRB and 
Health Authority, the Principal Investigator or designee will document all SAEs 
that occur following receipt of [68Ga]DOTATATE (whether or not related to 
study drug) to AAA. Such SAEs must be reported within 24 hours of Principal 
Investigator or designee becoming aware of the event.  All SAE information must 
be reported to https://www.adacap.com/contact-us/pharmacovigilance/. 
 
Additional and further requested information (follow-up or corrections to the 
original case) will be detailed and faxed/emailed to the same address and must 
include the following minimum information: The name and contact information of 
the reporter, the name of the study drug(s), a description of the reported SAE, with 
the subject identified by one or more of the following (subject initials, subject 
number  age, sex), an investigator assessment of study drug causality, and any 
additional data which would aid the review and causality assessment of the case 
including but not limited to the date of onset, severity, the time from administration 
of study drug(s) to start of the event, the duration and outcome of the event, any 
possible etiology for the event, and the final diagnosis or syndrome, if known. If 
AAA receives any individually identifiable health information collected or 
produced in the study, AAA shall use and disclose only for the purpose of 
complying with applicable laws, provided that all such uses are disclosed in the 
IRB-approved informed consent form.  AAA will use all reasonable efforts to 
protect the privacy and security of individually identifiable health information and 
will require its business partners to do so also.  AAA will not contact any study 
subjects, unless permitted by the informed consent form. 
 
6.5.5.1 General Definitions (from 21 CFR 312.32 (a)) 
Adverse Event (AE): An Adverse Event is an untoward medical occurrence 
associated with the use of the drug in humans, whether or not considered 


15 
drug related. For this study, the drug is [68Ga]DOTATATE and adverse 
events would include any events experienced by a study participant during 
the Adverse Event reporting period defined in Table 1 whether or not it was 
considered to be related to the [68Ga]DOTATATE.   At the conclusion of 
the imaging study, the imaging technologist will observe the patient and 
also inquire if they are back to their usual state of health.  If a negative 
answer is received, then the physician will be called to investigate this report 
as a possible adverse reaction. 
 
Adverse Reaction:  An Adverse Reaction is any adverse event caused by a 
drug. In this study, the drug is [68Ga]DOTATATE. 
 
Suspected adverse reaction means any adverse event for which there is a 
reasonable possibility that the IND 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. 
 
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. 
 
An adverse event or suspected adverse reaction is considered “serious” if, 
in the view of either the investigator or sponsor, it results in any of the 
following outcomes: Death, a life-threatening adverse event, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or 
significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or a congenital anomaly/birth defect. Important 
medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious 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. Examples of such medical events include: allergic 
bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
 
An adverse event or suspected adverse reaction is considered “life-
threatening” if, in the view of either the investigator or sponsor, its 
occurrence places the patient or subject at immediate risk of death. It does 
not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 


16 
 
Investigational Agent:  An investigational agent is any agent held under an 
Investigational New Drug (IND) application.  For purposes of this study, 
[68Ga]DOTATATE is the investigational agent. 
 
6.5.5.2 AE Reporting Requirements 
The investigators on this protocol will report any suspected adverse events 
that occur after [68Ga]DOTATATE administration and within the specified 
follow-up period to Dr. Galgano and they will work together to determine 
whether there was an adverse event or adverse reaction and the severity of 
the adverse event or reaction. 
 
All AEs will be followed by the investigators until resolution, stabilization, 
scientifically and clinically satisfactory explanation as to attribution and 
etiology is achieved, or until subject is lost to follow up.   
 
6.5.5.3 CAEPR/ASAE for [68Ga]DOTATATE 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) 
provides a single list of reported and/or potential adverse events (AE) 
associated with an agent using a uniform presentation of events by body 
system. The Agent Specific Adverse Event List (ASAEL) would include 
the expected adverse events associated with the use of [68Ga]DOTATATE. 
At this time, there are no reported AEs associated with the use of a 
[68Ga]DOTATATE in clinical studies. We will continue to update our 
CAEPR and ASAE lists as this study progresses, including by reviewing 
the literature and our in-house data safety monitoring.  If any are found, we 
will begin an ASAE list.  Any information on reported AEs for 
[68Ga]DOTATATE will be provided by the sponsor to all of the 
investigators on this protocol. 
 
6.5.5.4 Potential but Unexpected AE for [68Ga]DOTATATE 
There have been no reported AEs associated with the use of a 
[68Ga]DOTATATE in clinical studies. 
 
Other general risks for PET/CT and PET/MRI imaging include: 
 
 The injection site may become infected. 
 The dose might be extravasated into tissues surrounding the vein catheter 
leading to localized pain/discomfort. 
 
Radiation risks: [68Ga]DOTATATE injection contributes to lifetime 
radiation accumulation.  The smallest dosage for imaging and safe handling 
are used for these protocols. The organ and total body doses associated with 
[68Ga]DOTATATE imaging are comparable to those associated with other 
widely used clinical nuclear medicine procedures. The dose of the 
DOTATATE PET is approximately equal to 1.4 years of exposure to natural 


17 
background radiation. The dose of the CT scan is approximately equal to 2 
years of exposure to natural background radiation. 
 
6.5.5.5 Review of Safety Information 
As required by 21 CFR 312.32(b), the physician investigators will promptly 
review all information relevant to the safety of the drug. The physician 
investigators will also be providing much of this information to the local 
IRB as well for data safety and review monitoring.  The review will include 
determining whether there is a safety event over time and the causality.  
Reporting will be as described in Table 1. 
 
Characterization of the severity of an Adverse Event:  Adverse events will 
be graded as below. 
 
Grade:  Grade denotes the severity of the AE.  An AE is graded using the 
following categories: 
 Mild 
 Moderate 
 Severe 
 Life-threatening or disabling 
 Fatal 
 
NOTE:  Severity is graded on the Cancer Therapy Evaluation Program 
(CTEP) Common Terminology Criteria for Adverse Events (CTCAE) 
based scale for each adverse event. For example, an abnormal hemoglobin 
value is graded for severity from 1 to 5 [death] based upon where that value 
falls on the CTCAE scale of abnormal hemoglobin values.  “Severity” is 
NOT the same as “Seriousness.” All appropriate clinical areas should have 
access to a copy of the most current CTCAE and a copy of the CTCAE can 
be downloaded from (http://ctep.cancer.gov). 
 
Attribution of cause: The physician investigators will determine whether an 
adverse event was related to a medical treatment or procedure.  Definitions 
taken from our work with CTEP and NIH give the following definitions for 
“Attribution” that we will adopt for this IND study:  Attribution is a clinical 
determination, by the investigator, as to whether an AE is related to a 
medical treatment or procedure.  Attribution categories are: 
 Definite:     The AE is clearly related to a treatment or procedure  
 Probable:   The AE is likely related to a treatment or procedure 
 Possible:    The AE may be related to a treatment or procedure 
 Unlikely:     The AE is likely unrelated to a treatment or procedure 
 Unrelated:  The AE is clearly not related to a treatment or procedure 
 NOTE:  Attribution is part of the assessment of an adverse event.  
Determining that an event is ‘unlikely related’ or ‘unrelated’ to a study 
agent or procedure does NOT make the event unreportable, or disqualify 
the event as an AE.  As defined above, an AE is reportable as specified 


18 
herein if it occurred: “during the Adverse Event reporting period 
defined in the protocol, or by applicable guidance, regulation, or policy.” 
 
6.5.5.6 Adverse Event Reporting 
Expedited AE reporting for this study will be done through the Cancer 
Consortium, IRB and FDA and as required by FDA MedWatch. These 
requirements are briefly outlined in the table below.  
 
Table 1.  Reporting Requirements. 
 
Unexpected 
Expected 
 
Adverse Reaction (known or 
suspected attributable to the use of 
[68Ga]DOTATATE 
AE not 
attributable to 
[68Ga]DOTATATE 
AE, AR 
 
Serious including 
life-threatening (or 
death) 
Nonserious 
Life-Threatening or 
serious or not 
serious 
None are expected 
for 
[68Ga]DOTATATE 
Reporting 
Time 
Requirement 
to the FDA 
Report to FDA 
ASAP and within 
7 days of 
discovery of event  
Annual 
Continuation 
Review 
submission 
Annual 
Continuation 
Review submission 
Not applicable to 
[68Ga]DOTATATE 
Reporting 
Form for the 
FDA 
IND Safety report 
of potentially 
serious risk  
Annual Reports 
/ Case reports  
Annual Reports / 
Case reports 
Not applicable to 
[68Ga]DOTATATE 
Reporting 
Time 
Requirement 
to the local 
IRB 
Report to IRB 
ASAP within 10 
days of discovery 
of event (suspected 
is defined as 50% 
probability 
attributable to 
[68Ga]DOTATATE 
study) this also 
includes any 
increased risks 
with the study even 
without an AE 
At continuation 
review  time 
At continuation 
review time 
Not applicable to 
[68Ga]DOTATATE 
Reporting 
form for the 
IRB 
Expedited 
Reporting Form for 
Unanticipated 
Problems or 
Noncompliance 
and Adverse Event 
Reporting Form 
Form for 
Unanticipated 
Problems or 
Noncompliance, 
Case reports on 
continuation 
form, Data 
Safety 
Form for 
Unanticipated 
Problems or 
Noncompliance, 
Case reports on 
continuation form, 
Data Safety 
Monitoring Reports 
Not applicable to 
[68Ga]DOTATATE 


19 
Monitoring 
Reports 
 
6.5.5.7 Expedited Adverse Reaction Reporting Guidelines 
Life-threatening (or fatal) adverse reactions must be reported within 7 days 
to the FDA.  The FDA should be notified as soon as the adverse reaction is 
discovered by telephone or fax or email.  The instructions and forms are 
available 
at 
http://www.fda.gov/Safety/MedWatch/HowToReport/default.htm  
The 
report should be sent ASAP by mail and followed with a follow-up report. 
Individual IND safety reports to FDA are submitted on the Medwatch FDA 
Form 3500A as an “IND Safety Report”.  The form should be sent to The 
Director, Office of Generic Drugs in the Center for Drug Evaluation and 
Research at FDA.  The address and phone numbers are available at:  
http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm119100.htm. 
 
All life threatening adverse reactions reports are submitted to the FDA, THE 
UAB IRB and to all investigators.  A copy of the report is kept on file. 
 
6.5.6 Protection of Privacy 
Patients will be informed of the extent to which their confidential health 
information generated from this study may be used for research purposes. 
Following this discussion, they will be asked to sign the HIPAA form and informed 
consent documents. The original signed document will become part of the patient’s 
medical records, and each patient will receive a copy of the signed document. The 
use and disclosure of protected health information will be limited to the individuals 
described in the informed consent document. 
 
6.6 
Data Management 
All patient data will be anonymized and stored on encrypted password-protected computers 
with access only given to members of the research team. Standard precautions regarding 
HIPAA will be taken to avoid any breach in patient privacy. 
 
7.0 
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