Clinical trial NCT03463889
Conditions: Thyroid Gland Carcinoma
Sponsor: University of California, San Francisco
Start date: 2018-03-19; Completion date: 2020-10-31
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This pilot clinical trial studies how well Gallium-68 prostate specific membrane antigen positron emission tomography (PET) work in diagnosing patients with thyroid cancer. Diagnostic procedures, such as 68Ga-PSMA PET, may more accurately diagnose thyroid cancer and find out how far the disease has spread.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the feasibility and utility of Gallium Ga 68-labeled PSMA-11 (68Ga-PSMA) PET imaging in patients with thyroid cancer.

SECONDARY OBJECTIVES:

I. To assess the correlation between targeted molecular uptake of 68Ga-PSMA PET in thyroid cancer compared to areas identified as tumor by radioiodine uptake (in well-differentiated cancers) or fludeoxyglucose F-18 (18F-FDG) uptake (in poorly differentiated and/or radioiodine-negative cancers).

II. To determine and compare the sensitivity and specificity of 68Ga-PSMA PET to (18F-FDG) PET and/or radioiodine scintigraphy.

TERTIARY OBJECTIVES:

I. To determine if 68Ga-PSMA PET uptake is related to tumor differentiation and PSMA staining in tissue pathology when available.

II. To determine the correlation between standardized uptake value maximum (SUVmax) of target thyroid cancer lesions on 68Ga-PSMA PET and serum thyroglobulin levels.

OUTLINE:

Participants receive 68Ga-PSMA intravenously (IV) over 1-2 minutes and then undergo PET/MRI 60 minutes after injection. Patients may undergo a second PET/MRI 2-6 months after completion of first scan.

Arms: arm 1: Participants receive 68Ga-PSMA IV over 1-2 minutes and then undergo PET/MRI 60 minutes after injection. Patients may undergo a second PET/MRI 2-6 months after completion of first scan.
Interventions: intervention 1: Gallium Ga 68-labeled PSMA-11 intervention 2: Magnetic Resonance Imaging intervention 3: Positron Emission Tomography (PET)
Intervention descriptions: intervention 1: Given IV intervention 2: Undergo MRI in combination with PET intervention 3: Undergo PET in combination with MRI

Protocol documents:
Prot_SAP_000.pdf: 
Proprietary and Confidential
The information in this document is considered privileged and confidential, and may not be disclosed to others except 
to the extent necessary to obtain Institutional Review Board approval and informed consent, or as required by 
Federal and State laws.  Persons to whom this information is disclosed should be informed that this information is 
privileged and confidential and that it should not be further disclosed.
Gallium-68 Prostate Specific Membrane Antigen (68Ga-
PSMA) PET for Imaging of Thyroid Cancer: A Feasibility 
Study
Protocol Number:  CC #172016
Study Drug:  Gallium 68 PSMA
Version Number:  6.0
Version Date:  04-10-2019
IND Number: 127621
Principal Investigator
Robert Flavell, MD
Assistant Professor of Radiology
Department of Radiology and Biomedical 
Imaging  
University of California San Francisco
Co-Principal Investigator
Sue Yom, MD
Associate Professor
Departments of Radiation Oncology and 
Otolaryngology
University of California San Francisco
Co-Investigators
Courtney Lawhn Heath, MD  
Spencer C. Behr, MD 
Thomas Hope, MD 
Christine Glastonbury, MD
Chienying Liu, MD 
Patrick Ha, MD
Jonathan George, MD
Revision History
Version 6.0
04-10-2019
Version 5.0
12-17-2018
Version 4.0
09-25-2018
Version 3.0
08-29-2018
Version 2.0
Version 1.1
Version 1.0 
09-13-2017
05-30-2017
04-04-2017
NCT # 03463889


Protocol Signature Page
Protocol No.: 172016
Version Date: 04-10-2019
1.
I agree to follow this protocol version as approved by the UCSF Protocol Review Committee 
(PRC), Institutional Review Board (IRB), and Data Safety Monitoring Committee (DSMC). 
2.
I will conduct the study in accordance with applicable IRB requirements, Federal regulations, 
and state and local laws to maintain the protection of the rights and welfare of study 
participants. 
3.
I certify that I, and the study staff, have received the requisite training to conduct this 
research protocol. 
4.
I have read and understand the information in the Investigators’ Brochure (or Manufacturer’s 
Brochure) regarding the risks and potential benefits. I agree to conduct the protocol in 
accordance with Good Clinical Practices (ICH-GCP), the applicable ethical principles, the 
Statement of Investigator (Form FDA 1572), and with local regulatory requirements. In 
accordance with the FDA Modernization Act, I will ensure the registration of the trial on the 
www.clinicaltrials.gov website. 
5.
I agree to maintain adequate and accurate records in accordance with IRB policies, Federal, 
state and local laws and regulations.
Principal Investigator
Printed Name
Signature
Date


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Abstract
Title
Gallium-68 Prostate Specific Membrane Antigen (68Ga-PSMA) PET for 
Imaging of Thyroid Cancer: A Feasibility Study
Patient 
population
The study population will consist of patients with thyroid cancer.
Key Eligibility Criteria:
 
History of thyroid cancer.

Whole body 18F-FDG PET, I-123or I-131 scintigraphy within the 
past 360 days demonstrating uptake

Age 18 years or older at the time of study entry
Rationale for 
Study
Agents targeting prostate specific membrane antigen (PSMA) are under 
investigation for both imaging and therapy of prostate cancer. However, 
despite its name, PSMA expression is not specific to prostate, and is seen 
in a variety of normal tissues and cancers. In particular, recent case reports 
have demonstrated that 68Ga-PSMA ligands demonstrate uptake in thyroid 
cancer. Intriguingly, a recent case report of a patient with thyroid cancer 
demonstrated a greater sensitivity for metastatic lesions using 68Ga-PSMA 
as compared to 18F-FDG.  This suggests the potential use of PSMA PET as 
a diagnostic (and, in radioiodine-negative thyroid cancers, therapeutic) 
agent in patients with thyroid cancer.
Primary 
Objective
To determine the feasibility and utility of 68Ga-PSMA PET imaging in 
patients with thyroid cancer 
Secondary 
Objectives
1.
To assess the correlation between targeted molecular uptake of 
68Ga-PSMA-11 in thyroid cancer compared to areas identified as 
tumor by radioiodine uptake (in well-differentiated cancers) or 18F-
FDG uptake (in poorly differentiated and/or radioiodine-negative 
cancers). 
2.
To determine and compare the sensitivity and specificity of 68Ga-
PSMA-11 PET to 18F-FDG PET and/or radioiodine scintigraphy
Exploratory 
Objectives
1.
To determine if 68Ga-PSMA PET uptake is related to tumor 
differentiation and PSMA staining in tissue pathology when available
2.
To determine the correlation between SUVmax of target thyroid 
cancer lesions on 68Ga-PSMA PET and serum thyroglobulin levels.
Study Design
This is a single center pilot study investigating the use of 68Ga-PSMA PET in 
patients with thyroid cancer.
Number of 
patients
40 patients will be accrued over an approximate 24-month period.  It is 
estimated that all patients will have routine diagnostic imaging, and all 
patients will have elevated serum thyroglobulin.
Duration of 
Therapy
The study will involve a whole-body 68Ga-PSMA PET/MRI scan obtained at 
a single time point with optional repeat scan approximately 2-6 months after 
the first 68Ga-PSMA PET/MRI scan.


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Duration of 
Follow up
 n/a
Duration of 
study
The study will reach completion approximately 24 months from the time the 
study opens to accrual.
Imaging 
Agent
68Ga-PSMA-11 (also known as 68Ga-PSMA-HBED-CC)


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List of Abbreviations
AE
adverse event
CRC
Clinical Research Coordinator
CT
computerized tomography
CTCEA
Common Terminology Criteria for Adverse Events
CTEP
Cancer Therapy Evaluation Program
CTMS
Clinical Trial Management System
DSMC
Data and Safety Monitoring Committee
DSMP
Data and Safety Monitoring Plan
FCBP
female of childbearing potential
FDA
Food and Drug Administration
Ga
Gallium
GCP
Good Clinical Practice
HDFCCC
Helen Diller Family Comprehensive Cancer Center
IND
investigational new drug application
IP
investigational product
IRB
Institutional Review Board
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
NCI
National Cancer Institute
PRC
Protocol Review Committee (UCSF)
PSMA
prostate-specific membrane antigen
SD
stable disease
SD
standard deviation
SUV
Standardized Uptake Value


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Table of Contents
Protocol Signature Page ............................................................................................................0
Abstract
1
List of Abbreviations...................................................................................................................3
1
Introduction .........................................................................................................................6
1.1
Background on Indication .......................................................................6
1.2
Rationale for the Proposed Study...........................................................6
2
Objectives of the Study.......................................................................................................6
2.1
Primary ...................................................................................................6
2.2
Secondary ..............................................................................................6
2.3
Exploratory Objectives, Other Assessments ..........................................6
3
Study Design.......................................................................................................................7
3.1
Characteristics........................................................................................7
3.2
Number of Subjects ................................................................................7
3.3
Eligibility Criteria .....................................................................................7
3.3.1
Inclusion Criteria .................................................................................7
3.3.2
Exclusion Criteria ................................................................................7
3.4
Study Timeline........................................................................................7
3.4.1
Primary Completion.............................................................................7
3.4.2
Study Completion................................................................................7
4
Imaging Agent.....................................................................................................................8
5
Study Procedures and Observations ..................................................................................8
5.1
Dosage and Administration ....................................................................8
5.1.1
Screening Assessments......................................................................8
5.1.2
Study Period........................................................................................8
5.1.3
Pathology ............................................................................................9
5.1.4
Optional repeat scan...........................................................................9
6
Reporting and Documentation of Results .........................................................................12
6.1
Definitions.............................................................................................12
6.2
Evaluation of Safety..............................................................................12
6.3
Definitions of Adverse Events...............................................................12
6.3.1
Adverse Event...................................................................................12
6.3.2
Adverse reaction ...............................................................................12
6.4
Recording of an Adverse Event............................................................13
6.5
Follow-up of Adverse Events................................................................14
6.6
Expedited Reporting .............................................................................14
6.7
Image Processing and Analysis ...........................................................15
6.8
Determination of Sample Size and Accrual Rate .................................15
6.9
Interim Analyses and Stopping Rules...................................................15
6.10
Analyses Plans .....................................................................................15
7
Study Management...........................................................................................................16
7.1
Pre-study Documentation .....................................................................16
7.2
Institutional Review Board Approval.....................................................16
7.3
Informed Consent .................................................................................16


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7.4
Changes in the Protocol .......................................................................17
8
Protection of Human Subjects ..........................................................................................17
8.1
Protection from Unnecessary Harm .....................................................17
8.2
Protection of Privacy.............................................................................17
8.3
Data Safety Monitoring Plan.................................................................17
References
19
Appendices
20
Appendix 1
Performance Status Criteria............................................................................20


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1
Introduction
1.1
Background on Indication
Thyroid cancer is the most common endocrine malignancy, with approximately 62,000 new 
cases per year in the United States (1). The vast majority of thyroid cancers respond favorably 
to initial therapy with surgical resection and in some cases radioiodine ablation or external beam 
radiotherapy or a combination of these therapies. However, a subset of patients with aggressive 
and less differentiated thyroid cancer refractory to radioiodine therapy ultimately succumb to 
their illness, with approximately 2,000 deaths per year in the US (2). For patients with disease 
that is refractory to surgical management or radioiodine ablation, treatment options include 
external beam radiation and kinase inhibitors. Options for restaging of these patients with 
thyroglobulin elevation but negative iodine scintigraphy (TENIS syndrome) include 18F-FDG 
PET/CT and conventional anatomic imaging with ultrasound, CT, or MRI. Nevertheless, the 
prognosis for these patients remains poor. Therefore, there is an unmet clinical need for 
therapies to help slow the progression of disease in patients with aggressive forms of thyroid 
cancer. 
1.2
Rationale for the Proposed Study
Agents targeting prostate specific membrane antigen (PSMA) are under investigation for both 
imaging and therapy of prostate cancer (3,4). However, despite its name, PSMA expression is 
not specific to prostate, and is seen in a variety of normal tissues and cancers (5,6).  In 
particular, recent case reports have demonstrated that 68Ga-PSMA ligands demonstrate uptake 
in thyroid cancer (7-10).  Intriguingly, a recent case report of a patient with thyroid cancer 
demonstrated a greater sensitivity for metastatic lesions using 68Ga-PSMA as compared to 18F-
FDG (7).  This suggests the potential use of 68Ga-PSMA PET as a diagnostic (and, in 
radioiodine-negative thyroid cancers, therapeutic) agent in patients with aggressive forms of 
thyroid cancer.
2
Objectives of the Study
2.1
Primary

To determine the feasibility and utility of 68Ga-PSMA PET imaging in patients with thyroid 
cancer 
2.2
Secondary
1.
To assess the correlation between targeted molecular uptake of 68Ga-PSMA PET in 
thyroid cancer compared to areas identified as tumor by radioiodine uptake (in well-
differentiated cancers) or 18F-FDG uptake (in poorly differentiated and/or radioiodine-
negative cancers). 
2.
To determine and compare the sensitivity and specificity of 68Ga-PSMA PET to 18F-FDG 
PET and/or radioiodine scintigraphy
2.3
Exploratory Objectives, Other Assessments
1.
To determine if 68Ga-PSMA PET uptake is related to tumor differentiation and PSMA 
staining in tissue pathology when available
2.
To determine the correlation between SUVmax of target thyroid cancer lesions on 68Ga-
PSMA PET and serum thyroglobulin levels.


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3
Study Design
3.1
Characteristics
This is a single center pilot study in patients with thyroid cancer. Eligible participants will receive 
a one-time administration of 68Ga-PSMA-11 and undergo a whole-body PET/MRI imaging study. 
Patients may undergo an additional follow-up 68Ga-PSMA-11 PET/MRI 2-6 months after the 
initial imaging study, if they give consent.
3.2
Number of Subjects
The total sample size is 40 patients enrolled over approximately 24 months.
3.3
Eligibility Criteria
Patients must have baseline evaluations performed prior to the first dose of study drug and must 
meet all inclusion and exclusion criteria.  In addition, the patient must be thoroughly informed 
about all aspects of the study, including the study visit schedule and required evaluations and all 
regulatory requirements for informed consent.  The written informed consent must be obtained 
from the patient prior to enrollment.  The following criteria apply to all patients enrolled onto the 
study unless otherwise specified.
3.3.1 Inclusion Criteria
1.
History of thyroid cancer
2.
Whole body 18F-FDG PET/CT, I-123or I-131 scintigraphy within the past 360 days of the 
scheduled 68Ga-PSMA PET demonstrating uptake.
3.
Age 18 years or older at the time of study entry
4.
Creatinine </= 3.0 mg/dL
5.
Ability to understand a written informed consent document, and the willingness to sign it
3.3.2 Exclusion Criteria
1.
Patients who have had active infection within 15 days of study enrollment that may be 
considered to interfere with 68Ga-PSMA PET imaging by the study investigators.
2.
Patients who are unable to have placement of intravenous line access.
3.
Pregnant or breastfeeding women.
4.
Patients not capable of undergoing a PET/MRI study due to weight, claustrophobia, or 
inability to lie still for the duration of the exam.
3.4
Study Timeline
3.4.1 Primary Completion
The study is expected to reach primary completion 24 months from the time the study opens to 
accrual.
3.4.2 Study Completion
The study is expected to reach completion 24 months from the time the study opens to accrual.


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4
Imaging Agent
68Ga-PSMA is a radiopharmaceutical that will be produced in the Department of Radiology and 
Biomedical Imaging Radiopharmaceutical Facility. The radiopharmaceutical will be prepared in 
the same facility in which the administration will take place, the UCSF China Basin Imaging 
Center, using a germanium-68 generator.
5
Study Procedures and Observations
5.1
Dosage and Administration
68Ga-PSMA will be administered on an outpatient basis.  It will be administered at a single time 
point, intravenously, prior to PET imaging.  The one-time nominal injected dose will be approved 
by the UCSF Radiation Safety Committee (RSC) and will be 3 to 7 mCi..  A simultaneous whole 
body PET/MRI will be used for attenuation correction and anatomic localization of 68Ga-PSMA 
uptake and SUV calculation.  68Ga-PSMA is currently in use at UCSF under an IND in prostate 
cancer with over 300 patients injected and no significant adverse events.  Additionally, this 
radiotracer has been used safely in Europe with over a thousand studies performed without a 
significant adverse event.  For this protocol, 68Ga-PSMA will cross reference the currently active 
IND for prostate cancer that is being used at UCSF.  A neck MRI with gadolinium (MR) will be 
performed at the time of the PET imaging. Gadolinium contrast will not be administered if the 
patient cannot receive contrast based on Radiology Department guidelines.
5.1.1 Screening Assessments
The Screening procedures and assessments must be completed within 28 days of the Day 1 
Visit, unless otherwise noted. 
A written, signed, informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated.  A copy of the signed ICF will be given to the subject and a copy will 
be filed in the medical record.  The original will be kept on file with the study records.  
All patients who are consented will be registered in OnCore®, the UCSF Helen Diller Family 
Comprehensive Cancer Center Clinical Trial Management System (CTMS).  The system is 
password protected and meets HIPAA requirements.
In addition to OnCore, REDCap will be used to collect data for this study. REDCap is a secure, 
HIPAA-compliant, web-based system.

Complete medical history

Baseline standard staging diagnostic exams may be done approximately 360 days 
before PSMA PET as clinically indicated. Patients may receive staging scans and 68Ga-
PSMA PET imaging on the same day if the patient meets eligibility criteria for the study 
as assessed by the Principal Investigator prior to the completion of the scan.

Pregnancy testing in women of childbearing potential (WOCBP)

Creatinine

Thyroglobulin


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5.1.2 Study Period
5.1.2.1
68Ga-PSMA PET/MRI
Subjects will be injected with 68Ga-PSMA 
 and, if 
needed, transported to the imaging site.  After the biodistribution period (50 to 80 minutes after 
radiotracer injection), coverage for the scan will extend from the patient’s vertex through the 
thighs. 
A standard neck MRI will be performed concurrently with the PET/MRI. This MRI will be 
performed without and with gadolinium contrast intravenously. Gadolinium contrast will not be 
administered if the patient cannot receive contrast based on Radiology Department guidelines. 
A whole body (vertex to toes) MRI (PET/MRI) will be performed for attenuation correction and 
anatomic localization. Patients may be given lorazepam as needed, to keep them from feeling 
anxious during the scan. The entire imaging study will take roughly 60 minutes. Imaging will be 
performed at 
 UCSF 
.
No formal report of the findings from imaging studies will be created.  Each study will be 
reviewed by a board-certified nuclear medicine physician and a board-certified radiologist within 
two working days of the completion of the study.  68Ga-PSMA PET results will not be used for 
clinical care.  If any unexpected findings are visualized, these will be reported to the treating 
health care provider, who will then contact the patient if additional work-up needs to be 
performed.
5.1.3 Pathology
In those patients with adequate archival Formalin-Fixed Paraffin-Embedded (FFPE) tissue, 
analysis will be performed retrospectively when available after successful completion of 68Ga-
PSMA PET. 
5.1.4 Optional repeat scan
An optional follow up  68Ga-PSMA PET study may be obtained between 2 and 6 months after 
completion of the first PET. Optional PET will be performed to determine any interval changes in 
PSMA uptake and compare them to clinical changes including thyroglobulin. The potential for 
follow-up examination will be discussed and consented for during the original consent process. 
The study team will contact the patient after completion of the PET about repeat 
imaging.  Sections 5.1.2 and 5.1.3 will be followed during the follow-up imaging. 
A maximum number of two 68Ga-PSMA studies (initial and optional follow up) will be performed 
under this protocol.


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1.
Standard of care PET scan may be done up to 360 days before PSMA PET. Patients may receive staging scans and 68Ga-PSMA PET imaging on 
the same day if the patient meets eligibility criteria for the study as assessed by the Principal Investigator prior to the completion of the scan.
2.
Only required if patient agrees to optional follow-up 68Ga-PSMA PET.
Period/
Procedure
Screening
  
Imaging
Optional 
Imaging
Study Day/Visit 
Day
-28 to 1
D1
2-6 
months 
after 1st 
68Ga-
PSMA PET
Informed 
consent
X
AE assessment
X2
Concomitant 
medications
X
X
X2
Clinical 
procedures
Medical history 
including 
prior/concomitant 
systemic 
therapies for 
thyroid cancer
X
Laboratory 
procedures
Creatinine
X
Thyroglobulin
X
Pregnancy test 
(HCG) (WOCBP 
only)
X
Imaging 
procedures
Standard 
diagnostic scans 
as clinically 
indicated1
X1
68Ga-PSMA-11 
administration
X
X2
Whole body 
PET/MRI
X
X2


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6
Reporting and Documentation of Results
6.1
Definitions
Evaluable for toxicity
All patients will be evaluable for toxicity from the time of 68Ga-PSMA administration.
6.2
Evaluation of Safety
Analyses will be performed for all patients having received 68Ga-PSMA.  The study will use the 
CTCAE v4.0 for reporting of adverse events.
6.3
Definitions of Adverse Events
6.3.1 Adverse Event
An adverse event (also known as an adverse experience) is defined as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug 
related.  More specifically, an adverse event (can be any unfavorable and unintended sign (e.g., 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
drug, without any judgment about causality.  An adverse event can arise from any use of the 
drug (e.g., off-label use, use in combination with another drug) and from any route of 
administration, formulation, or dose, including an overdose. 
6.3.2 Adverse reaction
An adverse reaction is defined as any adverse event caused by the use of a drug.  Adverse 
reactions are a subset of all suspected adverse reactions for which there is reason to conclude 
that the drug caused the event.
6.3.2.1 Suspected 
A suspected adverse reaction is defined as 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” indicates that 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 an adverse reaction.
6.3.2.2 Unexpected 
An adverse event or suspected adverse reaction is considered unexpected if it is not listed in 
the investigator brochure or package insert(s), 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,” as used in this definition, 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.
Adverse events that would be anticipated to occur as part of the disease process are 
considered unexpected for the purposes of reporting because they would not be listed in the 
investigator brochure.  For example, a certain number of non-acute deaths in a cancer trial 


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would be anticipated as an outcome of the underlying disease, but such deaths would generally 
not be listed as a suspected adverse reaction in the investigator brochure.
Some adverse events are listed in the Investigator Brochure as occurring with the same class of 
drugs, or as anticipated from the pharmacological properties of the drug, even though they have 
not been observed with the drug under investigation.  Such events would be considered 
unexpected until they have been observed with the drug under investigation. For example, 
although angioedema is anticipated to occur in some patients exposed to drugs in the ACE 
inhibitor class and angioedema would be described in the investigator brochure as a class 
effect, the first case of angioedema observed with the drug under investigation should be 
considered unexpected for reporting purposes.
6.3.2.3 Serious
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

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 function

Congenital anomaly/birth defect
Important medical events that may not result in death, are 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.
6.3.2.4 Life-threatening
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. 
6.4
Recording of an Adverse Event
All grade 3 and above adverse events will be entered into OnCore®, whether or not the event is 
believed to be associated with use of the study drug.  Data about these events and their severity 
will be recorded using the NCI CTCAE v4.0.  
The Investigator will assign attribution of the possible association of the event with use of the 
investigational drug, and this information will be entered into OnCore® using the classification 
system listed below: 


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Relationship 
Attribution 
Description 
Unrelated
The AE is clearly NOT related to the 
intervention 
Unrelated to investigational 
drug/intervention
Unlikely
The AE is doubtfully related to the 
intervention 
Possible
The AE may be related to the intervention 
Probable
The AE is likely related to the intervention 
Related to investigational 
drug/intervention
Definite
The AE is clearly related to the intervention 
Signs or symptoms reported as adverse events will be graded and recorded by the Investigator 
according to the CTCAE.  When specific adverse events are not listed in the CTCAE they will be 
graded by the Investigator as none, mild, moderate or severe according to the following grades 
and definitions:
Grade 0
No AE (or within normal limits)
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated
Grade 2
Moderate; minimal, local, or noninvasive intervention (e.g., packing, cautery) 
indicated; limiting age-appropriate instrumental activities of daily living (ADL)
Grade 3:
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL
Grade 4:
Life-threatening consequences; urgent intervention indicated
Grade 5:
Death related to AE
6.5
Follow-up of Adverse Events
All adverse events will be followed with appropriate medical management until resolved.  
Patients removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event.  For selected adverse events for which administration of the 
investigational drug was stopped, a re-challenge of the subject with the investigational drug may 
be conducted if considered both safe and ethical by the Investigator.
6.6
Expedited Reporting 
Reporting to the Data and Safety Monitoring Committee
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and it is determined to be related either to the study drug(s) 
or to a study procedure, the Investigator or his/her designee must notify the DSMC Chair (or 
qualified alternate) within 1 business day of knowledge of the event.  The contact may be by 
phone or e-mail.
Reporting to UCSF Committee on Human Research (Institutional Review Board)
The Principal Investigator must report events meeting the UCSF IRB definition of “Unanticipated 
Problem” (UP) within 10 business days of his/her awareness of the event. 


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6.7
Image Processing and Analysis
A trained nuclear medicine physician blinded to results of tissue analysis will evaluate the 
reconstructed PET, MRI, and fused PET/MR images using a PET volume computer-assisted 
reading software package. A positive lesion on gallium PSMA-11 PET will be defined as a focus 
of activity with at least 1.5 times higher SUV compared with mediastinal blood pool that is not 
attributable to other etiologies of tracer distribution (e.g. excretion) or above liver background. A 
volume of interest (VOI) will be semiautomatically placed around each lesion, and the calculated 
maximum standard uptake value (SUVmax) will be recorded for each lesion.  Adjusted SUVmax 
data will then be averaged across all lesions within a given patient (SUVmax-avg) if needed. In 
order to avoid clustering effects, analysis will be limited to the five largest lesions per study.
6.8
Determination of Sample Size and Accrual Rate
Although this is a feasibility study, we will provide a sample size estimate based on the 
difference in sensitivities between 68Ga-PSMA PET and either 131I and 18F-FDG.  To provide an 
estimate of the needed sample size we assumed that half of the patients will be imaged with 131I 
and half the patients will be imaged using 18F-FDG PET within 360 days of the 68Ga-PSMA-11 
imaging study.  We will compare the sensitivity of both 131I and 18F-FDG to 68Ga-PSMA PET.   
Assuming that both 131I and 18F-FDG have a sensitivity of 0.65 and 68Ga-PSMA PET has a 
sensitivity of 0.90.  Our null hypothesis is that there is no difference between either 131I and 18F-
FDG and 68Ga-PSMA PET misclassification rates (H_null: 131I/18F-FDG_misclass = PSMA PET 
misclass = 65%). The alternative hypothesis is that the FET PET misclassification rate is lower 
(H_alt: PSMA PET misclass < 131I/18F-FDG_misclass = 65%). Given a power of 0.87, a 
significance level of 0.05, and a one-sided test, we will require 20 patients for comparison to 18F-
FDG and 20 patients for comparison to 131I.  This will result in a total sample size of 40.  The 
anticipated accrual rate is approximately 1 to 2 patients per month, leading to an estimated total 
accrual period of up to 18 to 24 months.
6.9
Interim Analyses and Stopping Rules
After each patient is imaged, the acquired data will be reviewed to determine the optimal image 
acquisition.  If 68Ga-PSMA uptake is not appreciated in any of the first five patients imaged, 
study accrual will be halted and the imaging protocol will be re-evaluated.  A sample size of five 
patients for interim analysis will allow for a preliminary analysis of image quality and ability of 
68Ga-PSMA PET to detect thyroid cancer metastases.  
6.10
Analyses Plans
The number of 68Ga PSMA-11 PET-positive lesions and number of overall thyroid cancer 
lesions detected by standard staging scans will be descriptively reported for each patient and 
correlated with the lesions observed in standard MRI imaging. In addition, the mean, range, and 
standard deviation of SUVmax (across all visualized lesions per patient) and SUVmax-avg (across 
all patients in the study cohort) will be descriptively reported.
For each lesion detected on 18F-FDG PET or radioiodine scintigraphy (131I), the presence or 
absence of 68Ga-PSMA-11 uptake will be reviewed and tabulated. Presence on either 131I and 
18F-FDG will be considered true positive disease.  If additional lesions are detected on 68Ga-
PSMA-11 as compared to 18F-FDG or 131I, the lesions will be characterized as either true or 
false positives in comparison to the appearance of the lesion on conventional imaging (thyroid 
ultrasound, CT and MRI). The gold standard for an individual lesion will be FDG or 131I, if the 
individual lesion is positive on either imaging study.  If the lesions are not seen on either FDG or 
131I, then consensus reading of conventional imaging will be performed to determine true and 


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false positive lesions.  The total number of lesions detected using each technique will be 
compared, and this data will be used to determine the sensitivity and specificity of 68Ga-PSMA-
11 for the detection of disease. If a larger number of lesions are detected using of 68Ga-PSMA-
11 compared to 18F-FDG PET and 131I, this provides promising preliminary data, which can be 
used to justify study in a larger clinical trial. 
The patient cohort will be dichotomized by thyroglobulin level. The mean SUVmax-avg between 
dichotomized subgroups will be compared using the non-parametric Mann-Whitney U test. The 
correlation between SUVmax on 68Ga-PSMA PET and thyroglobulin level as a continuous 
variable will also be determined using Pearson correlation method.
In those patients with adequate archival FFPE the correlation between SUVmax on 68Ga-PSMA 
PET and tumor PSMA expression will be explored using Pearson correlation method.   
7
Study Management
7.1
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 UCSF RSC and IRB approval is received. 
The Investigator must comply with the applicable regulations in Title 21 of the Code of Federal 
Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable regulatory 
requirements.  The IRB must comply with the regulations in 21 CFR §56 and applicable 
regulatory requirements.
7.2
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 UCSF IRB (UCSF Institutional Review Board).  Prior to obtaining IRB approval, 
the protocol must be approved by the Helen Diller Family Comprehensive Cancer Center Site 
Committee and by the Protocol Review Committee (PRC).  The initial protocol and all protocol 
amendments must be approved by the IRB prior to implementation.  
7.3
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. 


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7.4
Changes in the Protocol
Once the protocol has been approved by the UCSF 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 PRC and 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.  
The Study Chair and the UCSF study team will be responsible for updating any participating 
sites.
8
Protection of Human Subjects 
8.1
Protection from Unnecessary Harm 
Each clinical site is responsible for protecting all subjects involved in human experimentation. 
This is accomplished through the IRB mechanism and the process of informed consent. The 
IRB reviews all proposed studies involving human experimentation and ensures that the 
subject’s rights and welfare are protected and that the potential benefits and/or the importance 
of the knowledge to be gained outweigh the risks to the individual. The IRB also reviews the 
informed consent document associated with each study in order to ensure that the consent 
document accurately and clearly communicates the nature of the research to be done and its 
associated risks and benefits. 
8.2
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.
8.3
Data Safety Monitoring Plan
Data and Safety Monitoring Plan for a Non-therapeutic Institutional Study 
Oversight and Monitoring Plan
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for monitoring data quality and patient safety for 
all HDFCCC institutional clinical studies.  A summary of DSMC activities for this study includes: 
•
Review of patient data. 
•
Review of serious adverse events. 
•
      Auditing on a yearly basis. 
•
Minimum of a yearly regulatory audit.


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The UCSF HDFCCC Data and Safety Monitoring Committee (DSMC) is responsible for subject 
safety for all HDFCCC institutional clinical studies.  Nontherapeutic studies are characterized as 
low risk studies due to the study design, as there isn’t administration of drugs or complementary 
therapy that put the patient at significant risk.   Twenty percent of all enrolled subjects will be 
audited once per year. 
Monitoring and Reporting Guidelines
Investigators will conduct continuous review of data and patient safety at monthly Site 
Committee meetings.  The risk assessment for this type of trial is low; hence, the study would 
be audited only once per year, with 20 percent of the enrolled subject being selected for audit.
Review and Oversight Requirements
Adverse Event Monitoring
All clinically significant adverse events (AEs), whether or not considered to be expected or 
unexpected and whether or not considered to be associated with the use of the study drug, will 
be entered into OnCore®, UCSF’s Clinical Trial Management System.  
Adverse events are graded according to the Common Terminology Criteria for Adverse Events 
(CTCAE) as developed and revised by the Common Therapy Evaluation Program (CTEP) of the 
National Cancer Institute.  Adverse events are further given an assignment of attribution or 
relationship to treatment or medical procedure.  Attribution categories are:
•
Definite – The adverse event is clearly related to the investigational agent(s) or 
medical procedure.
•
Probable – The adverse event is likely related to the investigational agent(s) or 
medical procedure.
•
Possible – The adverse event may be related to the investigational agent(s) or 
medical procedure.
•
Unlikely – The adverse event is doubtfully related to the investigational agent(s) 
or medical procedure.
•
Unrelated – the adverse event is clearly not related to the investigational 
agent(s) or medical procedure.
All clinically significant adverse events entered into OnCore® will be reviewed on a monthly 
basis at the Site Committee meetings
Serious Adverse Event Reporting 
By definition, an adverse event is defined as a serious adverse event (SAE) according to the 
following criteria:
•
Death.


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•
Life-threatening (i.e., results in an immediate risk of death).
•
Requires inpatient hospitalization or prolongation of existing hospitalization.
•
Permanent or significant disability/incapacity.
•
Gives rise to a congenital anomaly/birth defect, or cancer, or any experience that 
suggests a significant hazard, contraindication, side effect, or precaution that 
may require medical or surgical intervention to prevent one of the outcomes 
listed above. 
•
Event occurring in a gene therapy study.
•
Event that changes the risk/benefit ratio of a study.
•
Any other event the Principal Investigator judges to be serious or which would 
suggest a significant hazard, contraindication, side effect, or precaution.
Serious Adverse Event reporting will be in accordance with the UCSF IRB Regulations and 
Code of Federal Regulation Title 21 Part 312.32.  The SAE will be reported on a Med Watch 
form. 
UCSF IRB website for guidance in reporting serious adverse events:
https://irb.ucsf.edu/adverse-event
FDA website for guidance in reporting serious adverse events:
www.fda.gov/Safety/MedWatch/HowToReport/default.htm
Med Watch forms and information:
www.fda.gov/medwatch/getforms.htm
All Serious Adverse Events are entered into OnCore®, as well as submitted to the IRB via 
iRIS®.  The SAEs are reviewed and monitored by the Data and Safety Monitoring Committee on 
an ongoing basis and discussed at DSMC meetings, which take place every six (6) weeks.  The 
date the SAE was sent to all required reporting agencies will be documented in OnCore®. 
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and is determined to be possibly, probably, or definitely 
related either to the investigational drug or any research related procedure, the Investigator or 
his/her designee must notify the DSMC Chair or Vice Chair within 1 business day.  The 
reporting procedure is by communication via phone or in person with written documentation of 
the one-on-one communication via e-mail, with a copy of the e-mail to the DSMC Manager.
Review of Adverse Event Rates


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If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in the 
Investigator Brochure or package insert) is noted in the study, the Principal Investigator will 
notify the DSMC at the time the increased rate is identified.  The report will indicate if the 
incidence of adverse events observed in the study is above the range stated in the Investigator 
Brochure or package insert.
If at any time the Investigator stops enrollment or stops the study due to safety issues, the 
DSMC Chair and DSMC Manager must be notified within 1 business day and the IRB must be 
notified within 10 business days.
Data and Safety Monitoring Committee Contacts:
DSMC Chair:
UCSF HDFCCC
San Francisco, CA 94158
DSMC Monitors:
UCSF HDFCCC
San Francisco, CA 94143


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